Pyrazolyl-ureas as kinase inhibitors

ABSTRACT

There are provided compounds of formula (I) as defined in the specification which are p38 MAP kinase inhibitors for use as medicaments for the treatment inter alia of inflammatory diseases.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/849,987, filed on Dec. 21, 2017, which is a continuation of U.S.patent application Ser. No. 15/118,708, filed on Aug. 12, 2016, which isthe U.S. National Stage of International Application No.PCT/GB2015/050401, filed on Feb. 13, 2015 and claims the benefit of U.S.Provisional Application No. 61/940,282, filed on Feb. 14, 2014 andclaims the benefit of U.S. Provisional Application No. 61/941,064, filedon Feb. 18, 2014, the contents of which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The invention relates to compounds which are inhibitors of the family ofp38 mitogen-activated protein kinase enzymes (referred to herein as p38MAP kinase inhibitors), for example the alpha and gamma kinase sub-typesthereof, and the Src family of tyrosine kinases, and to their use intherapy, including in pharmaceutical combinations, especially in thetreatment of inflammatory diseases, in particular inflammatory diseasesof the lung, such as asthma and COPD, as well as those of thegastrointestinal tract, such as ulcerative colitis, Irritable BowelDisease (IBD) and Crohn's disease and of the eye, such as uveitis.

BACKGROUND OF THE INVENTION

Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively), havebeen identified each displaying different patterns of tissue expressionin man. The p38 MAPK alpha and beta isoforms are found ubiquitously inthe body, being present in many different cell types. The alpha isoformis well characterized in terms of its role in inflammation. Althoughstudies using a chemical genetic approach in mice indicate that the p38MAPK beta isoform does not play a role in inflammation (O'Keefe, S. J.et al., J. Biol. Chem., 2007, 282(48):34663-71), it may be involved inpain mechanisms through the regulation of COX2 expression (Fitzsimmons,B. L. et al., Neuroreport, 2010, 21(4):313-7). These isoforms areinhibited by a number of previously described small molecular weightcompounds. Early classes of inhibitors were highly toxic due to thebroad tissue distribution of these isoforms which resulted in multipleoff-target effects of the compounds. Furthermore, development of asubstantial number of inhibitors has been discontinued due tounacceptable safety profiles in clinical studies (Pettus, L. H. andWurz, R. P., Curr. Top. Med. Chem., 2008, 8(16):1452-67). As theseadverse effects vary with chemotype, and the compounds have distinctkinase selectivity patterns, the observed toxicities may bestructure-related rather than p38 mechanism-based. More recently,compounds with greater potency and specificity for p3α/β MAPK have beendeveloped; however, levels of efficacy achieved in the treatment ofchronic inflammatory diseases, including rheumatoid arthritis (SCIO-469,Genovese et al., J. Rheumatol., 2011, 38:846-54; Pamapimod, Cohen etal., Arthritis Rheum., 2009, 60:335-344; BMS-582949, Schieven at al.,Arthritis Rheum., 2010, 62: Suppl. 10:1513) and COPD (Losmapimod, Watzat al., Lancet Resp. Mead., 2014:63-72) have been disappointing.Furthermore, it is noteworthy that a p38 MAPK inhibitor was found todeliver benefit for patients with IBD after one week's treatment whichwas not sustained over a four week course of treatment (BIRB-796,Schreiber, S. et al., Clin. Gastro. Hepatology, 2006, 4:325-334).

An important conclusion drawn from these studies is that use of a targetspecific kinase inhibitor may not be sufficient to achieve and sustaintherapeutic benefit in complex inflammatory diseases, wheredysregulation of multiple immuno-inflammatory pathways and biologicaladaption can by-pass blockade of a single target mechanism, resulting inthe loss of response. It can be argued that for complex inflammatorydisease such as COPD, rheumatoid arthritis and IBD, inhibitors thattarget a set of kinases that are critical for regulation of thedifferent immuno-inflammatory mechanisms linked to pathology will havegreater potential to achieve efficacy and a sustained therapeuticresponse.

The role of p38 MAPK-alpha in the regulation of inflammatory pathwayshas been investigated extensively and is well established. Less is knownabout the p38 MAPK gamma and delta isoforms, which, unlike the alpha andbeta isozymes are expressed in specific tissues and cells. The p38MAPK-delta isoform is expressed more highly in the pancreas, testes,lung, small intestine and the kidney. It is also abundant in macrophagesand detectable in neutrophils, CD4+ T cells and in endothelial cells(Shmueli, O. et al., Comptes Rendus Biologies, 2003,326(10-11):1067-1072; Smith, S. J. Br. J. Pharmacol., 2006, 149:393-404;Hale, K. K., J. Immunol., 1999, 162(7):4246-52; Wang, X. S. et al., J.Biol. Chem., 1997, 272(38):23668-23674.) Very little is known about thedistribution of p38 MAPK gamma although it is expressed more highly inbrain, skeletal muscle and heart, as well as in lymphocytes andmacrophages (Shmueli, O. et al., Comptes Rendus Biologies, 2003,326(10-11):1067-1072; Hale, K. K., J. Immunol., 1999, 162(7):4246-52;Court, N. W. et al., J. Mol. Cell. Cardiol., 2002, 34(4):413-26;Mertens, S. et al., FEBS Lett., 1996, 383(3):273-6). Evidence that thep38 MAPK-gamma and p38 MAPK-delta kinases are expressed inimmunologically important and pro-inflammatory cell types has raisedinterest in their functions relative to p38 MAPK-alpha. Selective smallmolecule inhibitors of p38 MAPK gamma and p38 MAPK delta are notcurrently available to assess the roles of these kinasespharmacologically, although one previously disclosed compound, BIRB-796,is known to possess pan-isoform inhibitory activity. The inhibition ofp38 MAPK gamma and delta isoforms is observed at higher concentrationsof the compound than those required to inhibit p38 MAPK alpha and p38beta (Kuma, Y., J. Biol. Chem., 2005, 280:19472-19479). In additionBIRB-796 also impaired the phosphorylation of p38 MAPKs or JNKs by theupstream kinase MKK6 or MKK4. Kuma discussed the possibility that theconformational change caused by the binding of the inhibitor to the MAPKprotein may affect the structure of both its phosphorylation site andthe docking site for the upstream activator, thereby impairing thephosphorylation of p38 MAPKs or JNKs.

p38 MAP kinase is believed to play a pivotal role in many of thesignalling pathways that are involved in initiating and maintainingchronic, persistent inflammation in human disease, for example, insevere asthma and in COPD (Chung, F., Chest, 2011, 139(6):1470-1479).There is now an abundant literature which demonstrates that p38 MAPkinase is activated by a range of pro-inflammatory cytokines and thatits activation results in the recruitment and release of additionalpro-inflammatory cytokines. For instance Smith describes the inhibitoryeffect of p38 MAP kinase inhibitors on TNFα release from human PBMCs.However, the production of some cytokines (IL-8 and GM-CSF) by lungtissue macrophages isolated from smokers and ex-smokers was relativelyinsensitive to p38α/β MAPK inhibitors and Smith suggests that theabundance of p38 MAPK-delta expressed in these cells might account forthe diminished effects of the compounds (Smith et al., Br. J.Pharmacol., 2006, 149:393-404). Risco at al. (Proc. Natl. Acad. Sci.U.S.A., 2012, 109:11200-11205) have used p38 MAPK-gamma and p38MAPK-delta gene knockout mice to investigate the roles of these p38isoforms in pathways regulating cytokine production by macrophages.These studies established that in mice both kinases are essential forinnate immune inflammatory responses including proinflammatory cytokineproduction. More recently, Criado G. et al., (Arthritis Rheum., 2014,66(5):1208-17) have demonstrated that in a mouse model of inflammatoryarthritis reduced disease severity in p38γ/δ−/− mice was associated withlower cytokine production and immunological activation than in normalcontrol mice, indicating that p38 MAPK gamma and p38 MAPK delta arecrucial regulators of inflammatory joint pathology. These findingssuggest that in addition to p38 MAPK alpha, p38 MAPK gamma and p38 MAPKdelta are potential therapeutic targets in complex diseases that involveinnate and adaptive immune responses such as COPD.

The use of inhibitors of p38 MAP kinase in the treatment of chronicobstructive pulmonary disease (COPD) has also been investigated. Smallmolecule inhibitors targeted to p38 MAPK α/β have proved to be effectivein reducing various parameters of inflammation in cells and in tissuesobtained from patients with COPD, who are generally corticosteroidinsensitive, (Smith, S. J., Br. J. Pharmacol., 2006, 149:393-404) aswell as in various in vivo animal models (Underwood, D. C. et al., Am.J. Physiol., 2000, 279: L895-902; Nath, P. et al., Eur. J. Pharmacol.,2006, 544:160-167). Irusen and colleagues have also suggested thepossible involvement of p38 MAPK α/β with corticosteroid insensitivityvia the reduction of binding affinity of the glucocorticoid receptor(GR) in nuclei (Irusen, E. et al., J. Allergy Clin. Immunol., 2002,109:649-657.). Clinical experience with a range of p38 MAP kinaseinhibitors, including AMG548, BIRB-796, VX702, SCIO469 and SCIO323 hasbeen described (Lee, M. R. and Dominguez, C., Current Med. Chem., 2005,12:2979-2994). COPD is a condition in which the underlying inflammationis reported to be substantially resistant to the anti-inflammatoryeffects of inhaled corticosteroids. Consequently, a superior strategyfor treating COPD would be to develop an intervention which has bothinherent anti-inflammatory effects and the ability to increase thesensitivity of the lung tissues of COPD patients to inhaledcorticosteroids. A recent publication of Mercado (Mercado, N., et al.,Mol. Pharmacol., 2011, 80(6):1128-1135) demonstrates that silencing p38MAPK γ has the potential to restore sensitivity to corticosteroids. P38MAPK alpha (Mercado, N. et al., PLoS ONE, 2012, 7(7):e41582) and JNK(Papi et al., J. Allergy Clin. Immunol., 2013, 132:1075-1085) have alsobeen reported to have roles in regulating corticosteroid insensitivityand Armstrong et al. (JPET, 2011, 338:732-740) have shown that the mixedp38 isoform inhibitor BIRB-796 and the corticosteroid dexamethasone havesynergistic anti-inflammatory effects on COPD alveolar macrophages.Consequently there may be a benefit for patients in the use of a lessp38 alpha-specific MAP kinase inhibitor for the treatment of COPD andsevere asthma.

Many patients diagnosed with asthma or with COPD continue to suffer fromuncontrolled symptoms and from exacerbations of their medical conditionthat can result in hospitalisation. This occurs despite the use of themost advanced, currently available treatment regimens, comprising ofcombination products of an inhaled corticosteroid and a long actingβ-agonist. Data accumulated over the last decade indicates that afailure to manage effectively the underlying inflammatory component ofthe disease in the lung is the most likely reason that exacerbationsoccur. Given the established efficacy of corticosteroids asanti-inflammatory agents and, in particular, of inhaled corticosteroidsin the treatment of asthma, these findings have provoked intenseinvestigation. Resulting studies have identified that some environmentalinsults invoke corticosteroid-insensitive inflammatory changes inpatients' lungs. An example is the response arising fromvirally-mediated upper respiratory tract infections (URTI), which haveparticular significance in increasing morbidity associated with asthmaand COPD.

Epidemiological investigations have revealed a strong associationbetween viral infections of the upper respiratory tract and asubstantial percentage of the exacerbations suffered by patients alreadydiagnosed with chronic respiratory diseases. Some of the most compellingdata in this regard derives from longitudinal studies of childrensuffering from asthma (Papadopoulos, N. G., at al., Paediatr. Respir.Rev., 2004, 5(3):255-260). A variety of additional studies support theconclusion that a viral infection can precipitate exacerbations andincrease disease severity. For example, experimental clinical infectionswith rhinovirus have been reported to cause bronchialhyper-responsiveness to histamine in asthmatics that is unresponsive totreatment with corticosteroids (Grunberg, K., et al., Am. J. Respir.Crit. Care Med., 2001, 164(10):1816-1822). Further evidence derives fromthe association observed between disease exacerbations in patients withcystic fibrosis and HRV infections (Wat, D., et al., J. Cyst. Fibros.,2008, 7:320-328.). Also consistent with this body of data is the findingthat respiratory viral infections, including rhinovirus, represent anindependent risk factor that correlates negatively with the 12 monthsurvival rate in paediatric, lung transplant recipients (Liu, M., etal., Transpl. Infect. Dis., 2009, 11(4):304-312).

TLR3 is an endosomal pathogen pattern recognition receptor that sensesviral dsRNA that is produced during viral infection. In human bronchialepithelial cells (BEAS2B) the TLR3 pathway is activated in response torhinovirus infection (RV1B and RV39) (Wang et al., J. Immunol., 2009,183:6989-6997). Inhaled dsRNA and rhinovirus infection evokeneutrophilic exacerbation in allergic mice with established experimentalasthma (Mahmutovic-Persson et al., Allergy, 2014, 69(3):348-358). In anallergic asthma model, rhinovirus-infected TLR3 knockout micedemonstrated reduced infiltration of neutrophils and macrophages intothe lungs and significantly lower airways inflammation when comparedwith TLR3 positive controls (Wang Q. et al., PLoS Pathog.,7(5):e1002070). Taken together these observations suggest thatactivation of the TLR3-pathway is likely to play an important role inthe development of airways inflammation and exacerbations of respiratorydisease in response to rhinovirus-mediated respiratory tract infections

In human rhinovirus infected cells the activation of TLR3 has been shownto involve the receptor-recruitment and activation of c-Src kinase whichmediates multiple downstream cellular effects. A small number of studieshave appeared that link the activation of cellular Src (Src1 or p60-Src)or Src family kinases to specific responses following infection withviruses. These include a report that adenovirus elicits a PI3 kinasemediated activation of Akt through a c-Src dependent mechanism. Sykkinase activity is reported to be controlled by c-Src as an upstreamkinase in HRV infection (Lau et al., J. Immunol., 2008, 180:870-880). Ithas also been suggested that Rhinovirus-39 induced IL-8 production inepithelial cells depends upon Src kinase activation (Bentley, J. K.,Newcomb, D. C., J. Virol., 2007, 81:1186-1194). Finally, it has beenproposed that activation of Src kinase is involved in the induction ofmucin production by rhinovirus-14 in epithelial cells and sub-mucosalglands (Inoue, D. and Yamaya, M., Respir. Physiol. Neurobiol., 2006,154(3):484-499).

It has been disclosed previously that compounds that inhibit theactivity of both c-Src and Syk kinases are effective agents againstrhinovirus replication (Charron, C. E. et al., WO 2011/158042) and thatcompounds that inhibit p59-HCK are effective against influenza virusreplication (Charron, C. E. et al., WO 2011/070369). Certain p38 MAPKinhibitors have also been described as inhibitors of the replication ofrespiratory syncitial virus (Cass, L. et al., WO 2011/158039).

For the reasons summarised above, compounds designed to treat chronicrespiratory diseases that combine inhibition of c-Src and p59-HCKkinases with the inhibition of p38 MAPKs, are expected to beparticularly efficacious.

In addition to playing key roles in cell signalling events which controlthe activity of pro-inflammatory pathways, kinase enzymes are now alsorecognised to regulate the activity of a range of cellular functions.Among those which have been discussed recently are the maintenance ofDNA integrity (Shilo, Y., Nature Reviews Cancer, 2003, 3:155-168) andco-ordination of the complex processes of cell division. An illustrationof recent findings is a publication describing the impact of a set ofinhibitors acting upon the so-called “Olaharsky kinases” on thefrequency of micronudeus formation in vitro (Olaharsky, A. J. et al.,PLoS Comput. Biol., 2009, 5(7):e1000446). Micronucleus formation isimplicated in, or associated with, disruption of mitotic processes andis therefore an undesirable manifestation of potential toxicity.Inhibition of glycogen synthase kinase 3α (GSK3α) was found to be aparticularly significant factor that increases the likelihood of akinase inhibitor promoting micronucleus formation. Recently, inhibitionof the kinase GSK3β with RNAi was also reported to promote micronucleusformation (Tighe, A. et al., BMC Cell Biology, 2007, 8:34).

It may be possible to attenuate the adverse effects arising from druginteractions with Olaharsky kinases, such as GSK3α, by optimisation ofthe close and/or by changing the route of administration. However, itwould be more advantageous to identify therapeutically useful moleculesthat demonstrate low or undetectable activity against these off-targetenzymes and consequently elicit little or no disruption of mitoticprocesses, as measured in mitosis assays.

It is evident from consideration of the literature cited hereinabovethat there remains a need to identify and develop new p38 MAP kinaseinhibitors that have improved therapeutic potential over currentlyavailable treatments. Desirable compounds are those that exhibit asuperior therapeutic index by exerting, at the least, an equallyefficacious effect as previous agents but, in one or more respects, areless toxic at the relevant therapeutic close. An objective of thepresent invention therefore, is to provide such novel compounds thatinhibit the enzyme activity of p38 MAP kinase, for example with certainsub-type specificities (particularly alpha and gamma), together withtyrosine kinases within the Src family (particularly c-Src) therebypossessing good anti-inflammatory properties, and suitable for use intherapy. Preferred embodiments of the invention are compounds thatexhibit weak or no inhibitory activity of Olaharsky kinases, such asGSK3α. Preferred embodiments of the invention are compounds that inhibitthe enzyme activity of p59-HCK. Preferred embodiments of the inventionare compounds that exhibit weak or no inhibitory activity of SYK kinase.

SUMMARY OF THE INVENTION

According to the invention, there is provided a compound of formula (I):

wherein:R¹ represents

Q represents N or CH;R², R^(2b) and R^(2c) are independently selected from hydrogen,hydroxyl, halogen, —C₁₋₆alkyl, —C₁₋₆ haloalkyl, C₃₋₅cycloalkyl;—C₁₋₃alkylene-OH, —OC₂₋₃alkylene-OH, —C₁₋₆alkoxy, —C₁₋₃alkylene-N—(C₁₋₃alkyl)₂, —N(C₁₋₃alkyl)₂, —SC₁₋₃alkyl and —C₁₋₃alkylene-S—C₁₋₃alkyl;R^(2d) and R^(2e) are defined as follows: either

-   -   (i) R^(2d) represents hydrogen, —C₁₋₈ alkyl in which 1 to 3        carbon atoms are optionally substituted by halogen (e.g. F),        —C₀₋₂alkylene-Cyc, —C₀₋₂alkylene-Het, —CH₂-J, —C≡C—CH₂-J,        —NR³R⁴, —OR⁵ or —CN; and R^(2e) represents hydrogen or —C₁₋₆        alkyl (e.g. methyl); or    -   (ii) R^(2e) represents —C₀₋₂alkylene-Cyc, —C₀₋₂alkylene-Het,        —CO—K-Cyc, —CO—K′-Het, —CO—K′-HetAr, —CH₂-J, —CO-J′, or —C₁₋₈        alkyl in which 1 to 3 carbon atoms are optionally substituted by        halogen (e.g. F); and R^(2d) represents hydrogen or —C₁₋₆ alkyl        (e.g. methyl); or    -   (iii) R^(2d) and R^(2e) are joined and together represent a        C₃₋₅alkylene chain in which one carbon atom of said alkylene        chain, not being in a position adjacent to the pyrazine ring, is        optionally replaced by O or NR^(2f) wherein R^(2f) represents H        or C₁₋₃alkyl and wherein a carbon atom of said alkylene chain is        optionally substituted by one or more groups selected from        halogen (e.g. F), oxo and methyl;        J and J′ independently represent a C₁₋₁₀ alkyl moiety in which        1, 2 or 3 carbon atoms are replaced by a heteroatom selected        from O and N provided that any two heteroatoms if present are        separated by at least two carbon atoms and wherein 1 or 2 carbon        atoms are optionally substituted by oxo and which moiety is        optionally substituted by 1 to 3 halogen (e.g. F) groups        provided that J′ does not represent OH;        K and K′ independently represent a bond or a C₁₋₁₀ alkylene        chain in which 1, 2 or 3 carbon atoms are optionally replaced by        a heteroatom selected from O and N provided that any two        heteroatoms if present are separated by at least two carbon        atoms and provided that neither K nor K′ represents O;        R³ and R⁴ independently represent H or —C₁₋₈ alkyl optionally        substituted by 1 to 3 groups selected from hydroxyl, C₁₋₃alkoxy,        hydroxyC₁₋₃alkyl and halogen (e.g. F) and wherein 1 or 2 carbon        atoms of said alkyl are optionally substituted by oxo; or R³ and        R⁴ are joined such that —NR³R⁴ together represents a 4-7        membered heterocyclic ring optionally substituted by one to        three groups selected from C₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy,        hydroxyC₁₋₃alkyl and halogen (e.g. F) in which a carbon atom        separated by at least two carbon atoms from the nitrogen atom is        optionally replaced by a heteroatom selected from O and N; and        wherein a methylene group is optionally substituted by oxo; or        R³ represents C₃₋₆cycloalkyl and R⁴ represents hydrogen;        R⁵ represents —C₁₋₈ alkyl optionally substituted by 1 to 3        groups selected from hydroxyl, C₁₋₃ alkoxy, hydroxyC₁₋₃alkyl and        halogen (e.g. F) and wherein 1 to 3 carbon atoms are optionally        substituted by halogen (e.g. F);        Het represents a 4 to 7 membered non-aromatic heterocyclic ring        containing 1 or 2 heteroatoms selected from O, S and N or an 8        to 10 membered non-aromatic bicyclic heterocyclic ring        containing 1, 2 or 3 heteroatoms selected from O, S and N in        either case optionally substituted by one to three groups        selected from C₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy,        hydroxyC₁₋₃alkyl-, C₁₋₃haloalkyl, halogen (e.g. F), oxo,        —N(C₁₋₃alkyl)₂, —C(═O)C₁₋₃alkyl, —C(═O)OC₁₋₃alkyl, —C₁₋₃        alkylene-N—(C₁₋₃alkyl)₂, —C₁₋₃ alkylene-O—C₁₋₃alkyl,        C₃₋₆cycloalkyl and a 4-6 membered non-aromatic heterocyclic ring        containing 1 or 2 heteroatoms selected from O, S and N        optionally substituted by methyl, provided that Het is not        directly attached to the pyrazine ring via a heteroatom and        wherein a methylene group is optionally substituted by oxo;        Cyc represents a 3 to 7 membered non-aromatic carbocyclic ring        optionally substituted by 1 to 3 groups selected from C₁₋₃alkyl,        hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen (e.g. F) and        wherein a methylene group is optionally substituted by oxo; and        HetAr represents a 5- or 6 membered heteroaromatic ring        containing 1 to 3 heteroatoms selected from O, N and S and        optionally substituted by one to three groups selected from C₁₋₃        alkyl, hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₄alkyl-, halogen and        C₁₋₃haloalkyl;        or a pharmaceutically acceptable salt thereof.

Compounds of formula (I) together with their pharmaceutically acceptablesalts are sometimes referred to herein as “compounds of the presentinvention” or similar.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows the effect of test compounds (Example 2 as a compound ofthe invention, and Reference Compound) on rhinovirus-induced IL-8Release in BEAS2B cells

DETAILED DESCRIPTION OF THE INVENTION

Alkyl groups may be branched or straight chain. C₁₋₈alkyl groups may forexample represent C₁₋₆alkyl, C₁₋₄alkyl or C₁₋₃alkyl. Exemplary alkylgroups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl andCH₂CHMe₂. In one embodiment alkyl refers to straight chain alkyl.

C₃₋₆cycloalkyl groups include cycloalkyl of 3-6 ring members which mayoptionally be substituted by methyl e.g. cyclopropyl, 1-Me-cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

Haloalkyl means an alkyl group substituted by one or more halogen atomse.g. 1, 2 or 3 halogen atoms. Halogen atoms are suitably Cl, Br or Fespecially F. Examples of haloalkyl include —CF₃ and CH₂CF₃.

Alkoxy as used herein refers to straight or branched chain alkoxy, forexample methoxy, ethoxy, propoxy, butoxy. Alkoxy as employed herein alsoextends to embodiments in which an oxygen atom (e.g. a single oxygenatom) is located within the alkyl chain, for example —C₁₋₃ alkylOC₁₋₃alkyl, such as —CH₂CH₂OCH₃ or —CH₂OCH₃. Thus in one embodiment thealkoxy is linked through carbon to the remainder of the molecule, forexample —C_(6-n)alkyl-O—C_(6-m)alkyl in which n=1-5, m=1-5 and n+m=2-6.In one embodiment the alkoxy is linked through oxygen to the remainderof the molecule, for example —OC₁₋₆ alkyl. In one embodiment thedisclosure relates to straight chain alkoxy. In one embodiment thealkoxy is linked through oxygen to the remainder of the molecule but thealkoxy group contains a further oxygen atom, for example —OCH₂CH₂OCH₃.

When alkyl groups may be substituted by halogen, they may suitably besubstituted by Br, Cl or F, especially Cl or F, particularly F. Examplesinclude CF₃ and CH₂CF₃.

Unless otherwise specified, alkylene as employed herein is a straightchain or branched chain carbon linking group, for example comprisingmethylenes, between two other moieties. In one embodiment alkylenemoieties are straight chain alkylene moieties.

It will be clear to persons skilled in the art that where is carbon atomis said to be replaced by a heteroatom the heteroatom may replace aprimary, secondary or tertiary carbon, that is a CH₃, —CH₂— or a —CH—,group, as technically appropriate and hydrogen or branching in the alkylor alkylene chain will fill the valency of the heteroatom as appropriateto the location.

Thus, for example, where a terminal primary carbon is replaced by anoxygen heteroatom the terminal group will be an alcohol.

Cyc groups may be fully saturated or partially unsaturated e.g. they maycontain one C═C bond. Suitably they are fully saturated.

Het groups may be fully saturated or partially unsaturated e.g. they maycontain one C═C bond or C═N bond. Suitably they are fully saturated.

Examples of 4-7 membered non-aromatic heterocyclic rings containing 1 or2 heteroatoms selected from O, S and N that Het may represent includeazetidine, pyrrolidine, piperidine, piperazine, morpholine, dioxane,tetrahydrofuran and thiomorpholine.

Examples of 8-10 membered non-aromatic bicyclic heterocyclic ringscontaining 1 or 2 heteroatoms selected from O, S and N that Het mayrepresent include octahydropyrrolo[1,2-a]pyrazine.

Hat substituents may, for example, include methyl, hydroxyl, methoxy,hydroxymethyl and fluorine, especially methoxy. In an embodiment, Hetdoes not bear a substituent. A further example of Het is thiomorpholine.Further exemplary Het substituents include oxo, —COOMe, —COMe, —CH₂OMe,NMe₂, and —CH₂CH₂OH. A further exemplary Het substituent is morpholinyl.

Examples of substituted Het moieties include 3-methoxy piperidin-1-yl,4-methoxypiperidin-1-yl, 3-methoxypyrrolidin-1-yl,3-hydroxypyrrolidin-1-yl, 1-methylpiperidin-3-yl,1-methylpiperidin-4-yl, 1-methylpyrrolidin-3-yl,4-hydroxypiperidin-1-yl, 3-hydroxypiperidin-1-yl,3,4-dihydroxypyrrolidin-1-yl, 2,6-dimethylmorpholin-4-yl,1-methyl-azetidin-3-yl, 4-methoxy-azetidin-1-yl,3-methoxymethyl-azetidin-1-yl, 3-methoxy-azetidin-1-yl,4-fluoro-azetidin-1-yl, 4-fluoropiperidin-1-yl,4,4-difluoropiperidin-1-yl, 3-(morpholin-4-yl)-tetrahydrofuran-3-yl,3-fluoropyrrolidin-1-yl, 3-fluoro-piperdin-1-yl,1-(2-hydroxyethyl)-piperidin-4-yl, 4-acetyl-piperazin-1-yl,4-carboxymethyl-piperazin-1-yl, 4-methylpiperazin-1-yl,5-oxo-1,4-diazepin-1-yl, 3-oxo-4-methyl-piperazin-1-yl,3-oxo-piperazin-1-yl, 3-diaminomethyl-pyrrolidin-1-yl,4-ethylpiperazin-1-yl, 4-dimethylamino-piperazin-1-yl,4-(2-dimethylaminoethyl)-piperazin-1-yl, 4-methyl-1,4-diazepin-1-yl,1-(2-methoxyethyl)piperidin-4-yl and 1,1-dioxothiomorpholin-1-yl.

Examples of moiety HetAr include 5 membered heteroaromatic rings such asthiophene, pyrrole, furan, imidazole, thiazole, thiadiazole, pyrazoleand tetrazole and 6 membered heteroaromatic rings such as pyridine,pyrimidine and pyrazine. Exemplary substituents for HetAr includemethyl, methoxy, halogen and trifluoromethyl. An example of asubstituted HetAr is 1-methyl-imidazol-2-yl.

In one embodiment of the invention, the compound of formula (I) is acompound of formula (Ia):

wherein:R¹ represents

Q represents N or CH;R^(2a), R^(2b) and R^(2c) are independently selected from hydrogen,hydroxyl, halogen, —C₁₋₃alkyl, —C₁₋₆haloalkyl, C₃₋₅cycloalkyl;—C₁₋₃alkylene-OH, —OC₂₋₃alkylene-OH, and —C₁₋₆alkoxy;R^(2d) and R^(2e) are defined as follows: either

-   -   (i) R^(2d) represents hydrogen, —C₁₋₈ alkyl in which 1 to 3        carbon atoms are optionally substituted by halogen (e.g. F),        —C₀₋₂alkylene-Cyc, —C₀₋₂alkylene-Het, —CH₂-J, —NR³R⁴, —OR⁵ or        —CN; and R^(2e) represents hydrogen or —C₁₋₆ alkyl (e.g.        methyl); or    -   (ii) R² represents —C₁₋₈ alkyl in which 1 to 3 carbon atoms are        optionally substituted by halogen (e.g. F), —C₀₋₂alkylene-Cyc,        —C₀₋₂alkylene-Het, —CO—K-Cyc, —CO—K′-Het, —CH₂-J, —CO-J′; and        R^(2d) represents hydrogen or —C₁₋₆ alkyl (e.g. methyl); or    -   (iii) R^(2d) and R^(2e) are joined and together represent a        C₃₋₅alkylene chain in which one carbon atom of said alkylene        chain, not being in a position adjacent to the pyrazine ring, is        optionally replaced by O or NR^(2f) wherein R^(2f) represents H        or C₁₋₃alkyl and wherein a carbon atom of said alkylene chain is        optionally substituted by one or more groups selected from        halogen (e.g. F), oxo and methyl;        J and J′ independently represent a C₁₋₇ alkyl moiety in which 1,        2 or 3 carbon atoms are replaced by a heteroatom selected from O        and N provided that any two heteroatoms if present are separated        by at least two carbon atoms and wherein 1 or 2 carbon atoms are        optionally substituted by oxo and which moiety is optionally        substituted by 1 to 3 halogen (e.g. F) groups provided that J′        does not represent OH;        K and K′ independently represent a bond or a C₁₋₇ alkylene chain        in which 1, 2 or 3 carbon atoms are optionally replaced by a        heteroatom selected from O and N provided that any two        heteroatoms if present are separated by at least two carbon        atoms and provided that neither K nor K′ represents O;        R³ and R⁴ independently represent H or —C₁₋₈ alkyl optionally        substituted by 1 to 3 groups selected from hydroxyl, C₁₋₃alkoxy,        hydroxyC₁₋₃alkyl and halogen (e.g. F) and wherein 1 or 2 carbon        atoms of said alkyl are optionally substituted by oxo; or R³ and        R⁴ are joined such that —NR³R⁴ together represents a 4-7        membered heterocyclic ring optionally substituted by one to        three groups selected from C₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy,        hydroxyC₁₋₃alkyl and halogen (e.g. F) in which a carbon atom        separated by at least two carbon atoms from the nitrogen atom is        optionally replaced by a heteroatom selected from O and N; and        wherein a methylene group is optionally substituted by oxo;        R⁵ represents —C₁₋₈ alkyl optionally substituted by 1 to 3        groups selected from hydroxyl, C₁₋₃ alkoxy, hydroxyC₁₋₃alkyl and        halogen (e.g. F) and wherein 1 to 3 carbon atoms are optionally        substituted by halogen (e.g. F);        Het represents a 4-7 membered non-aromatic heterocyclic ring        containing 1 or 2 heteroatoms selected from O, S and N        optionally substituted by one to three groups selected from        C₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen        (e.g. F) provided that Het is not directly attached to the        pyrazine ring via a heteroatom and wherein a methylene group is        optionally substituted by oxo; and        Cyc represents a 3-7 membered non-aromatic carbocyclic ring        optionally substituted by 1 to 3 groups selected from C₁₋₃alkyl,        hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen (e.g. F) and        wherein a methylene group is optionally substituted by oxo;        or a pharmaceutically acceptable salt thereof.

In relation to compounds of formula (I) and compounds of formula (Ia)(if appropriate):

Suitably Q represents CH.

When Q represents N, preferably it is in the meta position to the pointof attachment to the pyrazole ring (i.e. Q represents optionallysubstituted pyridine-3-yl).

When R¹ represents substituted pyridin-3-yl, suitably R^(2b) is hydrogenand R^(2a) is a substituent in the 6 position.

When R¹ represents substituted thiophen-2-yl, suitably R^(2c) is asubstituent in the 5 position.

When R¹ represents substituted thiophen-3-yl, suitably R^(2c) is asubstituent in the 5 position.

When Q represents CH, suitably R^(2b) is hydrogen and R^(2a) is asubstituent in the 4 position.

Suitably R^(2a) is not hydrogen. Thus suitably R^(2a) represents Cl, F,CF₃, —CH₂OH, —OH, —C₁₋₆ alkyl e.g. methyl, ethyl or isopropyl or C₁₋₆alkoxy e.g. methoxy, more suitably —CH₂OH, —OH, —C₁₋₆ alkyl e.g. methylor ethyl or C₁₋₆ alkoxy e.g. methoxy, most suitably R^(2a) representsmethyl or methoxy especially methyl. R^(2a) may also, for example,represent —CH₂CH₂OH, methoxymethyl-, methoxyethyl- or methoxyethoxy-.

Suitably R^(2b) represents hydrogen or methyl, especially hydrogen.

Suitably R^(2c) represents —C₁₋₆ alkyl, e.g. methyl.

Suitably R¹ represents phenyl or pyridinyl substituted by R^(2a) (andR^(2b) represents hydrogen) especially phenyl substituted by R^(2a).

Suitably R¹ represents 3-methyl-phenyl, 4-methyl-phenyl,4-methoxyphenyl, 6-methoxy-pyridin-3-yl, 5-methyl-thiophen-2-yl,5-methyl-thiophen-3-yl, 4-hydroxmethylphenyl, 4-hydroxyphenyl,3-methyl-4-methoxyphenyl, 4-isopropyl-phenyl, 4-ethylphenyl,4-chlorophenyl, 3-chloro-4-methoxyphenyl, 3-chlorophenyl,3-fluorophenyl, 3,4-dimethylphenyl or 3-trifluoromethyl-4-methylphenyl,

Further suitable R¹ moieties include 3-methoxyphenyl,3-thiomethylphenyl, 4-thiomethylphenyl, 6-(dimethylamino)pyridine-3-yl,6-methylpyridine-4-yl, 6-methoxypyridine-4-yl, 3-isopropylphenyl,3-fluoro-4-methoxyphenyl, 3-fluoro-4-ethoxyphenyl,3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl,3-methyl-4-(2-methoxyethoxy)phenyl, 3-ethylphenyl,3-hydroxymethylphenyl, 3-(2-hydroxyethyl)phenyl,3-methoxy-4-methylphenyl, 3-methoxy-5-methylphenyl,6-methyl-pyridin-3-yl, 3-methoxy-5-fluorophenyl, 4-fluorophenyl,3-methyl-4-ethoxyphenyl, 3-methyl-5-methoxyphenyl,3-methyl-5-fluorophenyl, 3-methoxymethylphenyl, 4-methoxymethylphenyl,3-(2-methoxyethoxy)phenyl, 3-dimethylaminomethylphenyl and4-dimethylaminomethylphenyl.

More suitably, R¹ represents 3-methyl-phenyl, 4-methyl-phenyl,4-methoxyphenyl, 6-methoxy-pyridin-3-yl, 5-methyl-thiophen-2-yl or5-methyl-thiophen-3-yl, most suitably 3-methyl-phenyl or4-methyl-phenyl, especially 4-methyl-phenyl.

Suitably J represents a C₁₋₇ alkyl moiety (e.g. a C₁₋₅ alkyl moiety) inwhich 1 or 2 (e.g. 1) carbon atoms are replaced by a heteroatom selectedfrom O and N provided that any two heteroatoms if present are separatedby at least two carbon atoms and wherein 1 carbon atom is optionallysubstituted by oxo.

In an embodiment, J represents NHCOMe, CONH₂, CONMe₂, CONHMe, OH or NH₂,especially CONHMe, OH or NH₂. Alternative examples of J include OMe,CH₂OMe, CH₂CH₂OMe, CH₂CH₂OH, CH₂OH and CONHCH₂CH₂OMe.

Suitably J′ represents a C₁₋₇ alkyl moiety (e.g. a C₁₋₅ alkyl moiety) inwhich 1 or 2 (e.g. 1) carbon atoms are replaced by a heteroatom selectedfrom O and N provided that any two heteroatoms if present are separatedby at least two carbon atoms and wherein 1 carbon atom is optionallysubstituted by oxo provided that J′ does not represent OH.

In an embodiment J′ represents NMe₂, NHMe or NHCH₂CH₂OMe, especiallyNHMe or NHCH₂CH₂OMe. Alternative examples of J′ include NHEt,NHCH₂CH₂OH, NMeCH₂CH₂CMe₂OH, N(CH₂CH₂OMe)₂, NHCH₂CMe₂OMe,NHCH₂CH₂OCHMe₂, NHCH₂CH₂OCMe₃, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂OMe,NMeCH₂CH₂CH₂OH, NMeCH₂CH₂OMe and NHCH₂CH₂CH₃.

Suitably the first atom of J′ is N.

Suitably K and K′ independently represent a bond or a C₁₋₄ alkylenechain in which 1 or 2 (e.g. 1) carbon atoms are optionally replaced by aheteroatom selected from O and N provided that any two heteroatoms ifpresent are separated by at least two carbon atoms and provided thatneither K nor K′ represents O;

In one embodiment K′ represents a bond. In another embodiment, K′represents NCH₂CH₂. Alternative examples of K′ include NH, NCH₂,NCH₂CH(OH)CH₂, NCH(Me)CH₂, NCH₂CH₂CH₂, NCH₂CMe₂ and NCMe₂CH₂.

K may, for example, represent the specific groups above mentioned forK′.

Suitably R³ and R⁴ independently represent H or —C₁₋₈ alkyl optionallysubstituted by 1 or 2 (e.g. 1) groups selected from hydroxyl,C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen (e.g. F) and wherein 1 carbonatom of said alkyl is optionally substituted by oxo; or R³ and R⁴ arejoined such that —NR³R⁴ together represents a 4-7 membered heterocyclicring optionally substituted by one to three groups selected fromC₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen (e.g. F)in which a carbon atom separated by at least two carbon atoms from thenitrogen atom is optionally replaced by a heteroatom selected from O andN; and wherein a methylene group is optionally substituted by oxo.

Suitably R³ and R⁴ independently represent H or —C₁₋₈ alkyl e.g.Independently represents C₁₋₄alkyl e.g. each represents methyl. Furtherexamples of R³ include ethyl and OCH₂OMe. When R³ and R⁴ are joined,suitably —NR³R⁴ represents -azetidin-1-yl, -pyrrolidin-1-yl,piperidin-1-yl, —N-morpholinyl or 4-methyl-piperazin-1-yl andsubstituted derivatives thereof such as 3-hydroxy-azetidin-N-yl and3-fluoro-azetidin-N-yl.

Suitably R⁵ represents —C₁₋₈ alkyl optionally substituted by 1 or 2(e.g. 1) groups selected from hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl andhalogen (e.g. F).

Suitably R⁵ represents C₁₋₈alkyl e.g. C₁₋₄alkyl such as methyl. Furtherexamples of R⁵ include CH₂CH₂OH and CH₂CHMe₂.

Suitably Het represents a 5-7 (e.g. 5-6) membered non-aromaticheterocyclic ring containing 1 or 2 heteroatoms selected from O and Noptionally substituted by 1 or 2 (e.g. 1) groups selected fromC₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen (e.g. F)provided that Het is not directly attached to the pyrazine ring via aheteroatom and wherein a methylene group is optionally substituted byoxo.

Suitably Het represents pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl or morpholinyl, especially pyrrolidinyl, piperidinyl ormorpholinyl.

Suitably Het is linked to —C₁₋₂alkylene in a —C₁₋₂alkyleneHet moiety viaa nitrogen atom. Suitably Het is linked to K′ in a —CO—K′-Het moiety viaa nitrogen atom.

Suitably Cyc represents a 3-6 (e.g. 3-5) membered non-aromaticcarbocyclic ring (especially a fully saturated ring) optionallysubstituted by 1 or 2 (e.g. 1) groups selected from C₁₋₃alkyl, hydroxyl,C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen (e.g. F) and wherein amethylene group is optionally substituted by oxo.

Suitably Cyc represents cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, especially cyclopropyl.

When R^(2e) represents —CO—K′-Het, examples include —CO-Het wherein Hetis selected from azetidine, pyrrolidine, piperidine, 4-methoxypiperidine and morpholinyl, in each case Het being attached to —CO— viaa nitrogen atom.

When R^(2d) represents —C≡C—CH₂-J, examples include —C≡C—CH₂—OMe.

When R^(2d) and R^(2e) are joined and together represent a C₃₋₅alkylenechain in which one carbon atom of said alkylene chain, not being in aposition adjacent to the pyrazine ring, is optionally replaced by O orNR^(2f) wherein R^(2f) represents H or methyl and wherein a carbon atomon said alkylene chain is optionally substituted by one or more groupsselected from F and methyl, examples include —CH₂CH₂OC(O)CH₂, —(CH₂)₃—,CH₂OCH₂, CH₂NHCH—, —CH₂)₄—, —CH₂CH₂OCH₂—, —CH₂CH₂NHCH₂—, —CH₂CH₂NMeCH₂—,—CH₂OCH₂CH₂, CH₂NHCH₂CH₂—, —(CH₂)₅— —CH₂CHFCH₂CH₂— and —CH₂CHMeCH₂CH₂.For example, R^(2d) and R^(2e) can be joined by a —(CH₂)₃— or a —(CH₂)₄—chain,

Suitably (i) R^(2d) represents —NMe₂, OMe, —OCH₂CH₂OH,3-hydroxy-azetidin-N-yl, 3-fluoro-azetidin-N-yl, methyl, ethyl,cyclopropyl, —CN, CH₂OH, CH₂CONH₂, CH₂CONHMe or CH₂CONMe₂ (more suitablymethyl, ethyl, cyclopropyl, —CN, CH₂OH, CH₂CONH₂, CH₂CONHMe orCH₂CONMe₂, most suitably methyl, ethyl, cyclopropyl or —CN) and R^(2e)represents H; or (ii) R² represents methyl, ethyl, cyclopropyl, —CH₂OH,—CONH(CH₂)₂—N-morpholinyl, —CO-pyrrolidin-N-yl, —CO-piperidin-N-yl,—CO-(4-methoxy)piperidin-N-yl, —CO-morpholin-N-yl, —CONMe₂, —CH₂NHCOMe—CH₂CONHMe, —CH₂CONMe₂, —CH₂CONH₂, —CONHMe, —CONH(CH₂)₂OMe or —CH₂NH₂(more suitably methyl, ethyl, cyclopropyl, —CH₂OH,—CONH(CH₂)₂—N-morpholinyl, —CO-pyrrolidin-N-yl,—CO-(4-methoxy)piperidin-N-yl, —CH₂CONHMe, —CONHMe, —CONH(CH₂)₂OMe or—CH₂NH₂) and R^(2d) represents H; or (iii) R^(2d) and R^(2e) eachrepresent H; or (iv) R^(2d) and R^(2e) each represent methyl.

Alternatively, suitably (v) R^(2d) represents cyclobutyl, cyclopentyl,pyrrolidin-1-yl, isopropyl, dimethylamino, amino, NHCOCH₂OMe, (CH₂)₂OMe,(CH₂)₃OMe, (CH₂)₃OH, 4-pyranyl, ethoxy, NHCHMe₂, morpholin-4-yl,NH-cyclopropyl, NHMe, OCH₂CH₂OH, OCH₂CHMe₂, 3-hydroxy-azetidin-1-yl,CH₂CH₂OH, n-propyl, CH₂CONHCH₂CH₂OMe, CH₂-morpholin-4-yl, C≡C—CH₂OMe, or1-methyl-piperidin-4-yl and R^(2e) represents hydrogen; or (vi) R^(2e)represents CONH(CH₂)₂OH, CONH(CH₂)₂-(3-methoxy)piperidin-1-yl,CO-(4-methoxy)piperidin-1-yl, CONMeCH₂CH₂OMe,CO-(3-methoxy)-pyrrolidin-1-yl, CO-(3-hydroxy)-pyrrolidin-1-yl,CONHCH₂CH₂CMe₂OH, CON(CH₂CH₂OMe)₂, CONHCH₂CMe₂OMe,CONHCH₂CH₂(piperidin-1-yl), CONH(1-Me)-piperidin-4-yl,CONHCH₂(1-Me)-piperidin-4-yl, CONH-(1-Me)-pyrrolidin-3-yl,CONHCH₂CH₂-(4-OH)piperidin-1-yl, CONHCH₂CH₂(2,6-dimethyl)morpholin-4-yl,CONHCH₂CH₂pyrrolidin-1-yl, CONHCH₂CH(OH)CH₂morpholin-4-yl,CONH-(1-Me)-piperidin-3-yl, CONH-(1-Me)-azetidin-3-yl,CONHCH₂CH₂-(2-Me)-imidazol-1-yl, CONHCH₂CH₂-(4-COOMe)-piperazin-1-yl,CONHCH₂CH₂-(4-OMe)-piperidin-1-yl,CONH-(3-morpholin-4-yl)-tetrahydrofuran-3-yl,CONHCH₂CH₂-(4,4-difluoro)-piperidin-1-yl,CONHCH₂CH₂-(3-OH)-piperidin-1-yl, CONHCH₂CH₂-(4-F)-piperidin-1-yl,CONHCH₂CH₂-(3-OH)-pyrolidin-1-yl, CONHCH₂CH₂-(3-OMe)-pyrrolidin-1-yl,CONHCH₂-(1-Me)-piperidin-4-yl, CONHCH₂CH₂-(3-F)-pyrrolidin-1-yl,CONHCH₂CH₂-(3-F)-piperidin-1-yl, CONHCH₂CH₂(4-acetyl)-piperazin-1-yl,CONH(1-CH₂CH₂OH)-piperidin-4-yl, OMe, CONHCH₂CH₂OMe,CO-(3-OH)-pyrrolidin-1-yl, CO-(4-OMe)-azetidin-1-yl, CONHCH₂CH₂OiPr,CONHCH₂CH₂Ot-Bu, CO-(3-OH)-pyrrolidin-1-yl, CO-(4-OH)-piperdin-1-yl,CONHCH₂CH₂CH₂OH, CO-azetidin-1-yl, CO-(4-Me)-piperazin-1-yl,CO-(4-F)-piperidin-1-yl, CO-(4-Me)-piperidin-1-yl, CONHCH₂CH₂CH₂OMe,CH₂CH₂CH₂OMe, CH₂OMe, CONHEt, CONHCH₂CH₂CH₃, CO-(4-F)-azetidin-1-yl,CH₂OMe, CO-(3-OMe)-pyrrolidin-1-yl, CONMeCH₂CH₂OMe,CO-(4-OMe)-piperdin-1-yl, CO-(2,6-di-Me)-morpholin-4-yl,CONMeCH₂CH₂CH₂OH, CO-(3-OMe)-azetidin-1-yl, CO-(3-CH₂OMe)-azetidin-1-yl,CONHCH₂CH₂CH₂OH, CO-(3-OH)-piperidin-1-yl, CO-(3-OMe)-piperidin-1-yl,CO-4-acetylpiperazine-1-yl, CO-(5-oxo-1,4-diazepane-1-yl,CO-(3-F)-pyrrolidin-1-yl, CO-1,1-dioxothiomorpolin-4-yl,CO-3-oxo-4-methyl-piperazin-1-yl, CO-(4,4-difluoro)-piperidin-1-yl,CO-(3,4-dihydroxy)-pyrrolidin-1-yl, CO-3-oxopiperazin-1-yl,CO-(3-dimethylamino)-pyrrolidin-1-yl, CONHCH₂CH₂(4-Me-piperazin-1-yl),CH₂-morpholin-1-yl, CONHCH₂CH₂(1-Me-piperdin-4-yl), CONHCH₂CH₂NMe₂,CONHCH₂CH₂morpholin-1-yl, CO-(4-Et)-piperazin-1-yl,CO-4-dimethylamino-piperazin-1-yl, CO-(4-CH₂CH₂NMe₂)piperazin-1-yl,CO-(4-methyl)-1,4-diazepan-1-yl,CO-(octahydropyrrolo[1,2-a]pyrazin-2-yl), CH₂(4-Me-piperazin-1-yl),CONHCHMeCH₂morpholin-1-yl, CONHCH₂CH₂CH₂morpholin-1-yl,CONHCH₂CH₂CH₂(4-Me-piperazin-1-yl), CONHCH₂CMe₂-morpholin-1-yl,CONH—(N—CH₂CH₂OMe-piperidin-4-yl), CO-(4-dimethylamino-piperidin-1-yl),CONHCMe₂CH₂(N-morpholinyl) or CONHCH₂(1-Me-imidazol-2-yl) and R^(2d)represents hydrogen; or (vii) R^(2d) represents cyclopropyl or ethyl andR^(2e) represents methyl; or (viii) R^(2d) represents methyl or ethyland R^(2e) represents ethyl.

In one embodiment, R^(2d) and R^(2e) both represent hydrogen. In anotherembodiment, R^(2d) and R^(2e) both represent methyl. In one embodimentR^(2e) represents ethyl and R^(2d) represents hydrogen.

Suitably R^(2d) and R^(2e) moieties do not contain any F atoms attachedto a carbon atom adjacent to the pyrazine ring.

Suitably R^(2f) represents H or methyl, especially H.

Exemplary compounds of formula (I) include:

-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(4-((2-((5-(aminomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   N-((5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)acetamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-methylpyrazine-2-carboxamide;-   2-(6-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-dimethylacetamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-dimethylpyrazine-2-carboxamide;-   1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyanopyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-2-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-morpholinoethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-methoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-methylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-methylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-2-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-2-yl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   2-(6-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N-methylacetamide;-   2-(5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-dimethylacetamide;-   2-(5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetamide;-   1-(3-(tert-butyl)-1-(5-methylthiophen-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   2-(6-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetamide;-   2-(5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N-methylacetamide;-   1-(3-(tert-butyl)-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(morpholine-4-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(5-methylthiophen-2-yl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(5-methylthiophen-3-yl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(4-chlorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-chloro-4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclobutylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopentylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;    and-   1-(3-(tert-butyl)-1-(4-methyl-3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;    and pharmaceutically acceptable salts of any one thereof.

Further exemplary compounds of formula (I) include:

-   5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamide;-   (S)-5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-methoxypiperidin-1-yl)ethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(pyrrolidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methoxypiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxy-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (S)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-isopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxy-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-hydroxy-3-methylbutyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-bis(2-methoxyethyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxy-2-methylpropyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-bis(2-methoxyethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(3-(methylthio)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(6-(dimethylamino)pyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(piperidin-1-yl)ethyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(1-methylpiperidin-4-yl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-((1-methylpiperidin-4-yl)methyl)pyrazine-2-carboxamide;-   (R)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(1-methylpyrrolidin-3-yl)pyrazine-2-carboxamide;-   (S)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(1-methylpyrrolidin-3-yl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(4-hydroxypiperidin-1-yl)ethylpyrazine-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-((2S,6R)-2,6-dimethylmorpholino)ethyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-(2-(pyrrolidin-1-yl)ethylpyrazine-carboxamide;-   (S)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-(2-hydroxy-3-morpholinopropylpyrazine-carboxamide;-   (S)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-(1-methylpiperidin-3-ylpyrazine-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-(1-methylazetidin-3-ylpyrazine-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-(2-(2-methyl-1H-imidazol-1-yl)ethylpyrazine-carboxamide;-   Methyl    4-(2-(5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)aminopyrazine-carboxamido)ethylpiperazine-1-carboxylate;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(4-methoxypiperidin-1-yl)ethyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-((3R,4R)-4-morpholinotetrahydrofuran-3-yl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-(2-(4,4-difluoropiperidin-1-yl)ethylpyrazine-carboxamide;-   (R)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methylpyridin-2-yl)amino)-N-(2-(3-hydroxypiperidin-1-yl)ethyl)pyrazine-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(4-fluoropiperidin-1-yl)ethyl)pyrazine-2-carboxamide;-   (R)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)pyrazine-2-carboxamide;-   (R)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-methoxypyrrolidin-1-yl)ethyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-((1-methylpiperidin-4-yl)methyl)pyrazine-2-carboxamide;-   (R)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-fluoropyrrolidin-1-yl)ethyl)pyrazine-2-carboxamide;-   (S)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-fluoropiperidin-1-yl)ethyl)pyrazine-2-carboxamide;-   N-(2-(4-acetylpiperazin-1-yl)ethyl)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-methoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(4-((2-((6-aminopyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   N-(6-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-2-methoxyacetamide;-   1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-methoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-2-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6-methoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-methoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-2-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(5-methylthiophen-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6-methoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(isopropylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-morpholinopyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(cyclopropylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(methylamino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(2-hydroxyethoxy)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-isobutoxypyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(3-hydroxyazetidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-isopropoxyethyl)pyrazine-2-carboxamide;-   N-(2-(tert-butoxy)ethyl)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide;-   (S)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-hydroxypiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(4-((2-((5-(azetidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(fort-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-ethyl-6-methylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6,7-dihydro-5H-cyclopenta[b]pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-isopropylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-hydroxypropyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methylpiperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(piperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6,7,8-tetrahydroquinoxalin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-diethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-methoxy-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethyl-5-methylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-(methylthio)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropyl-5-methylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(3-methoxypropyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(2-methoxyethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(3-hydroxypropyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(4-(2-methoxyethoxy)-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(3-methoxyprop-1-yn-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxyazetidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(2-hydroxyethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-fluoropiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-ethoxy-3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-ethoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methylpiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-methoxypropyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypropyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(methoxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-ethylpyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-propylpyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-fluoroazetidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(methoxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxy-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-ethoxy-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (S)-1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(methoxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-methylpyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)-N-methylpyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methoxypiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxy-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   2-(6-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N-(2-methoxyethyl)acetamide;-   1-(3-(tert-butyl)-1-(4-methoxymethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxy-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-hydroxypropyl)-N-methylpyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxyazetidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-(methoxymethyl)azetidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxy-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-methoxy-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-hydroxypropyl)pyrazine-2-carboxamide;-   (S)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(2-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (S)-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(4-((2-((5-(4-acetylpiperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(5-oxo-1,4-diazepane-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (S)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-fluoropyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(1,1-dioxidothiomorpholine-4-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methyl-3-oxopiperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-fluoropyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4,4-difluoropiperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-((3S,4S)-3,4-dihydroxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-((3R,4R)-3,4-dihydroxypyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-oxopiperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(4-ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluoro-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(2-methoxyethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (S)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (R)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-(dimethylamino)pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(4-methylpiperazin-1-yl)ethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(3-((dimethylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(morpholinomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(morpholinomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(2-methoxypyridin-4-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(1-methylpiperidin-4-yl)ethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(4-((dimethylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(dimethylamino)ethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methylpiperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-morpholinoethyl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-ethylpiperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-(dimethylamino)piperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methyl-1,4-diazepane-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (S)-1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(octahydropyrrolo[1,2-a]pyrazine-2-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   (S)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(1-morpholinopropan-2-yl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-morpholinopropyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-(4-methylpiperazin-1-yl)propyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methyl-2-morpholinopropyl)pyrazine-2-carboxamide;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(1-(2-methoxyethyl)piperdin-4-yl)pyrazine-2-carboxamide;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-ethylpiperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(4-(dimethylamino)piperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(morpholinomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(1-methylpiperidin-4-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea;-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methyl-1-morpholinopropan-2-yl)pyrazine-2-carboxamide;    and-   5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-((1-methyl-1H-imidazol-2-yl)methyl)pyrazine-2-carboxamide;    and pharmaceutically acceptable salts of any one thereof.

In an embodiment, the compound of formula (I) is not1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaor a pharmaceutically acceptable salt thereof.

Compounds of formula (I) may be prepared or employed in the form of apharmaceutically acceptable salt, including the therapeutically activenon-toxic acid addition salts that the compounds of formula (I) are ableto form. These pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the free base form with suchappropriate acids in a suitable solvent or mixture of solvents.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric acids and the like; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic acid and the like. Conversely said salt formscan be converted by treatment with an appropriate base into the freebase form. Other salts of acid compounds of formula (I) include metalsalts from periodic table groups 1 and 2 such as sodium, potassium,calcium and magnesium salts, and ammonium salts. These pharmaceuticallyacceptable salts can conveniently be obtained by treating the free acidform with such appropriate bases in a suitable solvent or mixture ofsolvents.

The invention provided herein extends to all stereoisomers of compoundsof formula (I). The term stereoisomers as employed herein refers toisomeric molecules that have the same molecular formula and sequence ofbonded atoms (constitution), but that differ only in thethree-dimensional orientations of their atoms in space.

As employed herein the definition of compounds of formula (I) isintended to include all tautomers of said compounds, and solvates ofsaid compounds (including solvates of salts of said compounds) unlessthe context specifically indicates otherwise. Examples of solvatesinclude hydrates.

The invention provided herein extends to prodrugs of the compound offormula (I), that is to say compounds which break down and/or aremetabolised in vivo to provide an active compound of formula (I).General examples of prodrugs include simple esters, and other esterssuch as mixed carbonate esters, carbamates, glycosides, ethers, acetalsand ketals.

In a further aspect of the invention there is provided one or moremetabolites of the compound of formula (I), in particular a metabolitethat retains one or more of the therapeutic activities of the compoundof formula (I). A metabolite, as employed herein, is a compound that isproduced in vivo from the metabolism of the compound of formula (I),such as, without limitation, oxidative metabolites and/or metabolitesgenerated, for example, from O-dealkylation.

The compounds of the disclosure include those where the atom specifiedis a naturally occurring or non-naturally occurring isotope. In oneembodiment the isotope is a stable isotope. Thus the compounds of thedisclosure include, for example deuterium containing compounds and thelike.

The disclosure also extends to all polymorphic forms of the compoundsherein defined.

A first process for preparing a compound of formula (I) or a protectedderivative thereof comprises reacting a compound of formula (II)

or a protected derivative thereofwherein LG¹ represents a leaving group;with a compound of formula (III)

or a protected derivative thereof;and optionally deprotecting the product to yield a compound of formula(I).

In compounds of formula (II), examples of leaving groups LG¹ includehalo (especially Cl, Br) and aryloxy-, especially phenoxy-.

Compounds of formula (II) may optionally be used in a form in whichsidechain R¹ is protected.

Compounds of formula (III) may optionally be used in a form in whichsidechain R^(2d) or R^(2e) are protected.

Suitable protecting groups and means for their removal are describedinfra.

Suitable conditions for the reaction of compounds of formula (II) and(III) include treating a mixture of (II) and (III) in a suitable solventsuch as THF, DCM or isopropyl acetate with triethylamine or Hunig's baseand warming the reaction to a temperature such as 40° C.

A second process for preparing a compound of formula (I) comprisesmodifying another compound of formula (I). Thus a compound of formula(I) having a certain R^(2d) or R^(2e) group may be converted to acompound of formula (I) having a different R^(2d) or R^(2e) group.

By way of illustration, a compound of formula (I) in which R^(2d)contains a carboxylic add group can be converted to a correspondingamide by reaction with an amine. Conditions for the reaction of an amineand an acid to form an amide are well known to a skilled person andinclude treating a mixture of the amine and the acid with a couplingagent such as HATU in a solvent such as DCM optionally in the presenceof a base such as Hunig's base. Other methods include conversion of theacid to an acid chloride or anhydride followed by treatment with anamine in the presence of a base such as Hunig's base in a solvent suchas DCM. Similarly, a compound of formula (I) in which R^(2d) contains aprimary or secondary amine group can be converted to a correspondingamide by reaction with an activated carboxylic acid (e.g. in the form ofan anhydride). Certain compounds of formula (I) in which R^(2e)represents —CO—K′-Het may be prepared from compounds of formula (I) inwhich R^(2e) represents CO-J′.

A third process for preparing a compound of formula (I) comprisesreacting a compound of formula (IV)

or a protected derivative thereof,with a compound of formula (V)

wherein LG² represents leaving group, such as halo and especially Cl ora protected derivative thereofand optionally deprotecting the product to yield a compound of formula(I).

Compounds of formula (IV) may optionally be used in a form in whichsidechain R¹ is protected.

Compounds of formula (V) may optionally be used in a form in whichsidechain R^(2d) or R^(2e) are protected.

Suitable protecting groups and means for their removal are describedinfra.

Suitable conditions for the reaction of compounds of formula (IV) and(V) include those normally employed for the Buchwald reaction i.e.treatment of a solution of (IV) and (V) in a solvent such as 1,4-dioxanewith a palladium source and ligand such as Pd₂(dba)₃ and BINAP and abase such as sodium tert-butoxide or cesium carbonate at elevatedtemperature.

Alternative ligands include diphenylphosphinoferrocene andtriphenylphosphine; alternative palladium sources include palladium (II)acetate and tetrakis(triphenylphosphine)palladium(0); alternative basesinclude lithium bis(trimethylsilyl)amide and potassium phosphate;alternative solvents include THF and toluene. For a wider range ofconditions, see Surry, D. S.; Buchwald, S. L. (2008), “Biaryl PhosphaneLigands in Palladium-Catalyzed Amination”, Angew. Chem. Int. Ed.47:6338-6361, and references therein.

A fourth process for preparation of compounds of formula (I) in whichR^(2e) represents —CO-J′ in which the atom of J′ attached to CO is Ncomprises reacting a compound of formula (VI)

with a compound of formula HNJ″ wherein J″ represents the remainder ofthe moiety J′. Suitable conditions for the reaction of a compound offormula (VI) with a compound of formula HNJ″ include treating a mixtureof HNJ″ and (VI) with a coupling agent such as HATU in a solvent such asDCM optionally in the presence of a base such as Hunig's base. Compoundsof formula HNJ″ are known or may be prepared by methods known to askilled person.

Compounds of formula (VI) may be prepared by methods analogous to thosedescribed herein for preparing compounds of formula (I).

Optionally a compound of formula (VI) or intermediates in the steps ofpreparation thereof which carry the —COOH substituted pyrazine may beprepared in a form in which said COOH group is protected, e.g. as analkyl ester such as a methyl or ethyl ester of the carboxylic acid. Thecarboxylic acid may be regenerated from an alkyl ester derivativethereof by treatment with base (e.g. LiOH).

Thus, for example, a compound of formula (VI) may be prepared byreaction of a compound of formula (II) with a compound of formula(III′):

Compounds of formula (III′) may be prepared by hydrolysis of thecorresponding alkyl ester derivative thereof (e.g. methyl esterderivative thereof) by treatment with base (e.g. LiOH).

Compounds of formula (II) may be prepared by reaction of a compound offormula (VII)

with a compound of formula LG¹C(═O)LG³ wherein LG³ represents a leavinggroup such as halo and especially Cl.

Suitable conditions for the reaction of a compound of formula (VII) witha compound of formula LG¹C(═O)LG³ where LG¹ is PhO and LG³ is Clcomprise treatment of a mixture of a solution of compound of formula(VII) in a solvent such as isopropyl acetate and an aqueous solution ofan inorganic base such as sodium carbonate with phenyl chloroformate.

Compounds of formula (VII) are known or may be prepared by methods topersons skilled in the art.

A first process for preparing a compound of formula (III) comprisesreducing a compound of formula (VIII)

Suitable conditions for the reduction of a compound of formula (VIII)include treatment with hydrogen gas over platinum on carbon catalyst.This reaction may be carried out at elevated pressure in a solvent suchas THF acidified with acetic acid. Alternatively it may be performed ina solvent such as DCM/MeOH under flow conditions using an H-cubehydrogenator.

This process is also suitable for preparing compounds of formula (III′)or an alkyl ester (e.g. the methyl ester) derivative of the —COOH groupthereof. In such a case an analogue of a compound of formula (VIII)having R^(2e)═COOH (or an alkyl ester e.g. the methyl ester derivativethereof) would be employed.

A second process for preparing a compound of formula (III) comprisesdeprotecting a compound of formula (IX)

wherein P₁ represents an amine protecting group.

Suitable protecting groups and means for their removal are describedinfra. A most suitable protecting group is Boc which can be removed bytreatment with acid such as TFA or HCl.

This process is also suitable for preparing compounds of formula (III′)or an alkyl ester (e.g. the methyl ester) derivative of the —COOH groupthereof. In such a case an analogue of a compound of formula (IX) havingR^(2e)═COOH (or an alkyl ester e.g. the methyl ester derivative thereof)would be employed. Such compounds are referred to herein as compounds offormula (IX′).

A process for preparing a compound of formula (IV) comprises reacting acompound of formula (X)

with a compound of formula (II).

Suitable conditions for the reaction of compounds of formula (X) and(II) include those mentioned above for the reaction of compounds offormula (II) and (III).

A first process for preparing a compound of formula (VIII) comprisesreacting a compound of formula (XI)

with a compound of formula (V)wherein LG² represents halogen, especially Cl.

Suitable conditions for the reaction of compounds of formula (XI) and(V) include those mentioned above for the reaction of compounds offormula (IV) and (V).

A second process for preparing a compound of formula (VIII) comprisesreacting a compound of formula (XII)

wherein Hal represents halogen, especially Clwith a compound of formula (XIII)

Suitable conditions for the reaction of compounds of formula (XII) and(XIII) include treatment of a solution of (XII) and (XIII) in a solventsuch as 1,4-dioxane with a palladium source and ligand such as Pd₂(dba)₃and BINAP and a base such as sodium tert-butoxide or cesium carbonate atelevated temperature.

This process is also suitable for preparing analogues of compounds offormula (VIII) referred to above having R^(2e) ═COOH (or an alkyl estere.g. methyl ester derivative thereof). In such a case an analogue of acompound of formula (XIII) having R^(2e)═COOH (or an alkyl ester e.g.the methyl ester derivative thereof) would be employed.

A third process for preparing a compound of formula (VIII) in which inwhich R^(2e) represents —CH₂-J and J represents —COJ^(a) (J^(a) beingthe remainder of moiety J) in which the atom of J^(a) attached to CO isN comprises reacting a compound of formula (XIVa)

with a compound of formula HNJ^(b) wherein J^(b) represents theremainder of moiety J^(a). Suitable conditions for the reaction of acompound of formula (XIVa) with a compound of formula HNJ^(b) includetreating a mixture of HNJ^(b) and (XIVa) with a coupling agent such asHATU in a solvent such as DCM optionally in the presence of a base suchas Hunig's base. Compounds of formula HNJ^(b) are known or may beprepared by methods known to a skilled person.

A fourth process for preparing a compound of formula (VIII) in which inwhich R^(2d) represents —CH₂-J and J represents —COJ^(a) (J^(a) beingthe remainder of moiety J) in which the atom of J^(a) attached to CO isN comprises reacting a compound of formula (XIVb)

with a compound of formula HNJ^(b) wherein J^(b) represents theremainder of moiety J^(a). Suitable conditions for the reaction of acompound of formula (XIVb) with a compound of formula HNJ^(b) are thesame as those described above for the reaction of a compound of formula(XIVa) with a compound of formula HNJ^(b).

Compounds of formula (XIVa) and (XIVb) may be prepared by methodsanalogous to those described herein for preparing compounds of formula(VIII). Conveniently a compound of formula (XIVa) or (XIVb) may beprepared in protected form, e.g. as an alkyl ester such as a methyl orethyl ester of the carboxylic acid. The carboxylic acid may beregenerated from an alkyl ester derivative thereof by treatment withbase (e.g. LiOH). Thus a compound of formula (XIVa) or (XIVb) in whichthe —COOH group is protected as an alkyl (e.g. methyl) ester may beprepared by reaction of a compound of formula (XI) with an analogue of acompound of formula (V) having R^(2e) or R^(2d)=CH₂COOalkyl (e.g.alkyl=methyl).

A first process for preparing compounds of formula (IX) comprisesreacting a compound of formula (XV)

with a compound of formula (V)wherein LG² represents halogen, especially Cl.

Suitable conditions for the reaction of compounds of formula (XV) and(V) are the same as those described above for the reaction of compoundsof formula (XI) and (V).

This process is also suitable for preparing compounds of formula (IX′)(being compounds of formula (IX) having R^(2e)═COOH or an alkyl estere.g. the methyl ester derivative thereof). In such a case an analogue ofa compound of formula (V) having R^(2e) ═COOH (or an alkyl ester e.g.the methyl ester derivative thereof) would be employed. Such compoundsare referred to herein compounds of formula (XI′).

A second process for preparing compounds of formula (IX) comprisesreacting a compound of formula (XVI)

wherein Hal represents halogen, especially Clwith a compound of formula (XIII)

Suitable conditions for the reaction of compounds of formula (XVI) and(XIII) are the same as those described above for the reaction ofcompounds of formula (XII) and (XIII).

This process is also suitable for preparing compounds of formula (IX′)(being compounds of formula (IX) having R^(2e)═COOH or an alkyl estere.g. the methyl ester derivative thereof). In such a case an analogue ofa compound of formula (XIII) having R^(2e)═COOH (or an alkyl ester e.g.the methyl ester derivative thereof) would be employed. Such compoundsare referred to herein compounds of formula (XIII′).

Certain compounds of formula (IX) in which R^(2e) represents CO—K-Cyc orCO—K′-Het in which the first atom of K or K′ is N may also be preparedfrom corresponding compounds of formula (IX′) in which R^(2e)═COOH bystandard amide formation processes (i.e. by reaction of said compound offormula (IX′) or an activated derivative thereof with a compound offormula HNK^(c) wherein K^(c) represents the remainder of moietyR^(2e)).

Certain compounds of formula (IX) in which R^(2d) represents —CH₂-J andJ represents —COJ^(a) (J^(a) being the remainder of moiety J) in whichthe atom of J^(a) attached to CO is N may also be prepared fromcorresponding compounds of formula (IX″) in which R^(2d)═CH₂COOH bystandard amide formation processes (i.e. by reaction of said compound offormula (IX″) or an activated derivative thereof with a compound offormula HNJ^(b) wherein J^(b) represents the remainder of moiety J^(a)).Compounds of formula (IX″) may be prepared from compounds of formula(XIVb) in the form of its alkyl ester (e.g. the methyl ester) viaprocesses described herein (i.e. reduction of the NO₂ group to thecorresponding amine, protection of the amine, and hydrolysis of theester).

Compounds of formula (XI) may be prepared as shown in the scheme below:

The reagents of this process are known compounds. Mitsunobu conditionsinclude treatment of a mixture of a phenol and an alcohol withtriphenylphosphine and diisopropylazodicarboxylate in a solvent such asTHF. For a wider range of conditions, see Swamy, K. C.; Kumar, N. N.;Balaraman, E.; Kumar, K. V. (2009). “Mitsunobu and Related Reactions:Advances and Applications” Chem. Rev. 109(6):2551-2651, and referencestherein.

Compounds of formula (X) may be prepared by reduction of compounds offormula (XI). Suitable conditions include those mentioned above forreduction of compounds of formula (VIII).

Compounds of formula (XII) may be prepared as shown in the scheme below:

The reagents of this process are known compounds. Mitsunobu conditionsinclude those given above.

Compounds of formula (XV) may be prepared as shown in the scheme below:

wherein LG⁴ is a leaving group such as halo, especially Cl.

The reagents of this process are known compounds. Alkylation conditionsinclude treatment of a mixture of a phenol and an alkyl halide with abase such as cesium or potassium carbonate in a solvent such asacetonitrile or DMF optionally at elevated temperature.

Compounds of formula (XVI) may be prepared as shown in the scheme below:

wherein LG⁵ is a leaving group such as those mentioned above for LG⁴.

The reagents of this process are known compounds. Alkylation conditionsinclude those given above.

In general, compounds of formula (V), (XI′), (XIII) and (XIII′) areeither known or may be prepared by methods known to the skilled person.Specific methods for preparing compounds of formula (V) and (XIII) thatmay be mentioned include treatment of a compound of formula (V) whereR^(2e) is COOH with an amine to form an amide. Suitable conditions forthis transformation include conversion of the acid to the acid chloridewith a chlorinating agent such as oxalyl chloride followed by treatmentwith an amine in the presence of a base such as Hunig's base in asolvent such as DCM.

Protecting groups may be required to protect chemically sensitive groupsduring one or more of the reactions described above, to ensure that theprocess is efficient. Thus if desired or necessary, intermediatecompounds (including compounds of formula (II) to (V) as highlightedabove as well as compounds of formula (VI) to (XVI)) may be protected bythe use of conventional protecting groups. Protecting groups and meansfor their removal are described in “Protective Groups in OrganicSynthesis”, by Theodora W. Greene and Peter G. M. Wuts, published byJohn Wiley & Sons Inc; 4^(th) Rev Ed., 2006, ISBN-10: 0471697540. Thusexemplary amine protecting groups include Boc which may be removed byTFA and exemplary alcohol protecting groups are THP which may be removedby HCl.

Compounds of formula (III), (III′), (VI), (VIII), (IX), (XIVa) and(XIVb) are novel and certain compounds of formula (V) and (XIII) arenovel. These novel compounds, together with their salts (includingpharmaceutically acceptable salts) are claimed as aspects of theinvention.

The compounds of formula (I) are p38 MAP kinase inhibitors (especiallyinhibitors of the alpha subtype) and in one aspect the compounds of thepresent invention are provided for use as a medicament e.g. in thetreatment of inflammatory diseases, for example COPD and/or asthma.

Surprisingly, in at least some embodiments, the compounds of formula (I)exhibit a long duration of action and/or persistence of action incomparison to other previously disclosed allosteric p38 MAP kinaseinhibitors such as, for example, BIRB-796 (Pargellis, C et al., NatureStruct. Biol., 2002, 9(4):268-272).

In one embodiment the compounds of formula (I) do not strongly inhibit,or bind to GSK 3α, for example they have an IC₅₀ value against GSK 3a of1000 nM or greater; such as 1,500, 2,000, 3,000, 4,000, 5,000, 6,000,7,000, 8,000, 9,000 or 10,000 nM or greater.

In one embodiment the compounds of formula (I) have inhibitory activityagainst GSK 3α at least 10 times (e.g. at least 100 times) weaker thanthat against p38MAPKα (i.e. the IC₅₀ value against GSK 3α is at least 10times (e.g. at least 100 times) that of the IC₅₀ value againstpMAPK38α).

Persistence of action as used herein is related to the dissociation rateor dissociation constant of the compound from the target (such as areceptor). A low dissociation rate may lead to persistence.

A low dissociation rate in combination with a high association ratetends to provide potent therapeutic entities.

The compounds of formula (I) are expected to be potent in vivo.

Typically, the prior art compounds developed to date have been intendedfor oral administration. This strategy involves optimizing thepharmacokinetic profile of drug substances in order to achieve anadequate duration of action. In this manner a sufficiently high drugconcentration is established and maintained between closes to providesustained clinical benefit. The inevitable consequence of this approachis that all bodily tissues, and especially the liver and the gut, arelikely to be exposed to supra-therapeutically active concentrations ofthe drug, whether or not they are adversely affected by the diseasebeing treated.

An alternative strategy is to design treatment paradigms in which thedrug is closed directly to the inflamed organ, that is, to exploittopical administration. Whilst this approach is not suitable fortreating all chronic inflammatory diseases, it has been exploited inlung disorders, such as asthma and COPD; in skin diseases, for exampleagainst atopic dermatitis and psoriasis; for nasal conditions, typifiedby allergic rhinitis; and in gastrointestinal diseases, such asulcerative colitis, IBD and Crohn's disease and inflammatory diseases ofthe eye, such as uveitis.

In topical therapy, one way in which efficacy can be achieved is by theuse of a drug that has a sustained duration of action and is retained inthe relevant organ, thereby minimizing the risk of systemic toxicity.Alternatively, in some cases, a formulation can be developed thatgenerates a “reservoir” of the active drug which is available to sustainits desired effects. The first approach is exemplified by theanticholinergic drug tiotropium (Spiriva). This compound is administeredtopically to the lung as a treatment for COPD, and has an exceptionallyhigh affinity for its target receptor resulting in a very slow off rateand consequently displays a sustained duration of action.

In one aspect of the disclosure the compounds of formula (I) isparticularly suitable for topical delivery, such as topical delivery tothe lungs, in particular for the treatment of respiratory disease, forexample chronic respiratory diseases such as COPD and/or asthma.

In one embodiment the compounds of formula (I) is suitable forsensitizing patients to treatment with a corticosteroid who have becomerefractory to such treatment regimens.

The compounds of formula (I) may have antiviral properties, for examplethe ability to prevent the infection of cells (such as respiratoryepithelial cells) with a picornavirus, in particular a rhinovirus,influenza or respiratory syncytial virus.

Thus the compounds are thought to be antiviral agents, in particularsuitable for the prevention, treatment or amelioration of picornavirusinfections, such as rhinovirus infection, influenza or respiratorysyncytial virus.

In one embodiment the compounds of formula (I) are able to reduceinflammation induced by viral infection, such as rhinovirus infectionand in particular viral infections that result in the release ofcytokines such as IL-8, especially in vivo. This activity may, forexample, be tested in vitro employing a rhinovirus induced IL-8 assay asdescribed in the Examples herein.

In one embodiment the compounds of formula (I) are able to reduce ICAM1expression induced by rhinovirus, especially in vivo. ICAM1 is thereceptor mechanism used by so-called major groove rhinovirus serotypesto infect cells. This activity may be measured, for example by a methoddescribed in the Examples herein.

It is expected that the above properties render the compounds of formula(I) particularly suitable for use in the treatment (includingprophylaxis) of exacerbations of inflammatory diseases, in particularviral exacerbations, or in the treatment of viral infections, inpatients with one or more chronic conditions such as congestive heartfailure, COPD, asthma, diabetes, cancer and/or in immunosuppressedpatients, for example post-organ transplant. Such use may be incombination with anti-viral agents such as zanamivir, oseltamivir (forexample oseltamivir phosphate), peramivir or laninamivir.

In general, the compounds of formula (I) may be useful in the treatmentof one or more conditions having an inflammatory component which,suitably, may be treated by topical or local therapy.

In particular, the compounds of formula (I) may be useful in thetreatment of one or more respiratory disorders including COPD (includingchronic bronchitis and emphysema), asthma, paediatric asthma, cysticfibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis,rhinitis and sinusitis, especially asthma, or COPD (including chronicbronchitis and emphysema).

Thus the compounds of formula (I) may be useful in the treatment of lunginflammation (and symptoms thereof) in subjects suffering from cysticfibrosis.

The compounds of formula (I) may be useful in the treatment of eyediseases or disorders including keratoconjunctivitis sicca (dry eye),allergic conjunctivitis, conjunctivitis, diabetic retinopathy, macularoedema (including wet macular oedema and dry macular oedema),post-operative cataract inflammation or, particularly, uveitis(including posterior, anterior and pan uveitis).

The compounds of formula (I) may be useful in the treatment of skindiseases or disorders including allergic dermatitis, contact dermatitis,atopic dermatitis or psoriasis.

The compounds of formula (I) may be useful in the treatment ofgastrointestinal diseases or disorders including ulcerative colitis, IBDor Crohn's disease.

The compounds of formula (I) may be useful in the treatment of jointdiseases or disorders including rheumatoid arthritis or osteoarthritisand particularly inflamed joints secondary to such conditions.

The compounds of formula (I) may be useful in the treatment of cancersincluding cancer of the stomach and in the inhibition of the growth andmetastasis of tumours including lung cancers such as non-small cell lungcarcinoma, gastric carcinoma, colorectal carcinomas and malignantmelanoma.

It is also expected that the compounds of formula (I) may be useful inthe treatment of certain other conditions including periodontitis,gingivitis and pharyngitis.

Compounds of formula (I) may also re-sensitise the patient's conditionto treatment with a corticosteroid, when the patient's condition hasbecome refractory to the same.

Furthermore, the present invention provides a pharmaceutical compositioncomprising a compound according to the disclosure optionally incombination with one or more pharmaceutically acceptable diluents orcarriers.

Diluents and carriers may include those suitable for parenteral, oral,topical, mucosal and rectal administration.

The present invention also provides a process for preparing such apharmaceutical composition (for example a pharmaceutical composition forparenteral, oral, topical, mucosal or rectal administration), saidprocess comprising mixing the ingredients.

As mentioned above, such compositions may be prepared e.g. forparenteral, subcutaneous, intramuscular, intravenous, intra-articular orperi-articular administration, particularly in the form of liquidsolutions or suspensions; for oral administration, particularly in theform of tablets or capsules or in the form of liquid solutions orsuspensions; for topical e.g. pulmonary or intranasal administration,particularly in the form of powders, aqueous solutions or suspensions,nasal drops or aqueous or non-aqueous aerosols, and for transdermaladministration e.g. patches, creams, ointments; for mucosaladministration e.g. to buccal, sublingual or vaginal mucosa, and forrectal administration e.g. in the form of a suppository, cream, ointmentor foam.

The compositions may conveniently be administered in unit or multi-dosedosage forms and may be prepared by any of the methods well-known in thepharmaceutical art, for example as described in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,(1985). Formulations for parenteral administration may contain asexcipients sterile water or saline, alkylene glycols such as propyleneglycol, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, hydrogenated naphthalenes and the like. Formulationsfor nasal administration may be solid and may contain excipients, forexample, lactose or dextran, or may be aqueous or oily solutions orsuspensions for use in the form of nasal drops or metered sprays. Forbuccal administration typical excipients include sugars, calciumstearate, magnesium stearate, pregelatinated starch, and the like.

Compositions suitable for oral administration may comprise one or morephysiologically compatible carriers and/or excipients and may be insolid or liquid form. Tablets and capsules may be prepared with bindingagents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, orpoly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch,calcium phosphate, sorbitol, or glycine; lubricants, such as magnesiumstearate, talc, polyethylene glycol, or silica; and surfactants, such assodium lauryl sulfate. Liquid compositions may contain conventionaladditives such as suspending agents, for example sorbitol syrup, methylcellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or ediblefats; emulsifying agents such as lecithin, or acacia; vegetable oilssuch as almond oil, coconut oil, cod liver oil, or peanut oil;preservatives such as butylated hydroxyanisole (BHA) and butylatedhydroxytoluene (BHT). Liquid compositions may be encapsulated in, forexample, gelatin to provide a unit dosage form.

Solid oral dosage forms include tablets, two-piece hard shell capsulesand soft elastic gelatin (SEG) capsules.

A dry shell formulation typically comprises of about 40% to 60% w/wconcentration of gelatin, about a 20% to 30% concentration ofplasticizer (such as glycerin, sorbitol or propylene glycol) and about a30% to 40% concentration of water. Other materials such aspreservatives, dyes, opacifiers and flavours also may be present. Theliquid fill material comprises a solid drug that has been dissolved,solubilized or dispersed (with suspending agents such as beeswax,hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug invehicles or combinations of vehicles such as mineral oil, vegetableoils, triglycerides, glycols, polyols and surface-active agents.

Suitably a compound of formula (I) is administered topically to thelung, eye or bowel. Hence we provide according to the invention apharmaceutical composition comprising a compound of the presentinvention optionally in combination with one or more topicallyacceptable diluents or carriers.

Topical administration to the lung may be achieved by use of an aerosolformulation. Aerosol formulations typically comprise the activeingredient suspended or dissolved in a suitable aerosol propellant, suchas a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFCpropellants include trichloromonofluoromethane (propellant 11),dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane(propellant 12). Suitable HFC propellants include tetrafluoroethane(HFC-134a) and heptafluoropropane (HFC-227). The propellant typicallycomprises 40%-99.5% e.g. 40%-90% by weight of the total inhalationcomposition. The formulation may comprise excipients includingco-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitantrioleate and the like). Other possible excipients include polyethyleneglycol, polyvinylpyrrolidone, glycerine and the like. Aerosolformulations are packaged in canisters and a suitable close is deliveredby means of a metering valve (e.g. as supplied by Bespak, Valois or 3Mor alternatively by Aptar, Coster or Vari).

Topical administration to the lung may also be achieved by use of anon-pressurised formulation such as an aqueous solution or suspension.These may be administered by means of a nebuliser e.g. one that can behand-held and portable or for home or hospital use (ie non-portable).The formulation may comprise excipients such as water, buffers, tonicityadjusting agents, pH adjusting agents, surfactants and co-solvents.Suspension liquid and aerosol formulations (whether pressurised orunpressurised) will typically contain the compound of the invention infinely divided form, for example with a D₅₀ of 0.5-10 μm e.g. around 1-5μm. Particle size distributions may be represented using D₁₀, D₅₀ andD₉₀ values. The D₅₀ median value of particle size distributions isdefined as the particle size in microns that divides the distribution inhalf. The measurement derived from laser diffraction is more accuratelydescribed as a volume distribution, and consequently the D₅₀ valueobtained using this procedure is more meaningfully referred to as a Dv₅₀value (median for a volume distribution). As used herein Dv values referto particle size distributions measured using laser diffraction.Similarly, D₁₀ and D₉₀ values, used in the context of laser diffraction,are taken to mean Dv₁₀ and Dv₉₀ values and refer to the particle sizewhereby 10% of the distribution lies below the D₁₀ value, and 90% of thedistribution lies below the D₉₀ value, respectively.

Topical administration to the lung may also be achieved by use of adry-powder formulation. A dry powder formulation will contain thecompound of the disclosure in finely divided form, typically with a massmean diameter (MMAD) of 1-10 μm or a D₅₀ of 0.5-10 μm e.g. around 1-5μm. Powders of the compound of the invention in finely divided form maybe prepared by a micronization process or similar size reductionprocess. Micronization may be performed using a jet mill such as thosemanufactured by Hosokawa Alpine. The resultant particle sizedistribution may be measured using laser diffraction (e.g. with aMalvern Mastersizer 2000S instrument). The formulation will typicallycontain a topically acceptable diluent such as lactose, glucose ormannitol (preferably lactose), usually of comparatively large particlesize e.g. a mass mean diameter (MMAD) of 50 μm or more, e.g. 100 μm ormore or a D₅₀ of 40-150 μm. As used herein, the term “lactose” refers toa lactose-containing component, including α-lactose monohydrate,β-lactose monohydrate, α-lactose anhydrous, β-lactose anhydrous andamorphous lactose. Lactose components may be processed by micronization,sieving, milling, compression, agglomeration or spray drying.Commercially available forms of lactose in various forms are alsoencompassed, for example Lactohale® (inhalation grade lactose; DFEPharma), InhaLac®70 (sieved lactose for dry powder inhaler; Meggle),Pharmatose® (DFE Pharma) and Respitose® (sieved inhalation gradelactose; DFE Pharma) products. In one embodiment, the lactose componentis selected from the group consisting of α-lactose monohydrate,α-lactose anhydrous and amorphous lactose. Preferably, the lactose isα-lactose monohydrate.

Dry powder formulations may also contain other excipients. Thus in oneembodiment a dry powder formulation according the present disclosurecomprises magnesium or calcium stearate. Such formulations may havesuperior chemical and/or physical stability especially when suchformulations also contain lactose.

A dry powder formulation is typically delivered using a dry powderinhaler (DPI) device. Example dry powder delivery systems includeSPINHALER®, DISKHALER®, TURBOHALER®, DISKUS®, SKYEHALER®, ACCUHALER® andCLICKHALER®. Further examples of dry powder delivery systems includeECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER,BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN,ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIELdry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN,PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.

In one embodiment a compound of the present invention is provided as amicronized dry powder formulation, for example comprising lactose of asuitable grade.

In one embodiment a compound of the present invention is provided as amicronized dry powder formulation, comprising lactose of a suitablegrade and magnesium stearate, filled into a device such as DISKUS.Suitably, such a device is a multiclose device, for example theformulation is filled into blisters for use in a multi-unit dose devicesuch as DISKUS.

In another embodiment a compound of the present invention is provided asa micronized dry powder formulation, for example comprising lactose of asuitable grade, filled into hard shell capsules for use in a single dosedevice such as AEROLISER.

In another embodiment a compound of the present invention is provided asa micronized dry powder formulation, comprising lactose of a suitablegrade and magnesium stearate, filled into hard shell capsules for use ina single dose device such as AEROLISER.

In another embodiment compounds of the present invention are provided asa fine powder for use in an inhalation dosage form wherein the powder isin fine particles with a D₅₀ of 0.5-10 μm e.g. around 1-5 μm, that havebeen produced by a size reduction process other than jet millmicronisation e.g. spray drying, spray freezing, microfluidisation, highpressure homogenisation, super critical fluid crystallisation,ultrasonic crystallisation or combinations of these methods thereof, orother suitable particle formation methods known in the art that are usedto produce fine particles with an aerodynamic particle size of 0.5-10μm. The resultant particle size distribution may be measured using laserdiffraction (e.g. with a Malvern Mastersizer 2000S instrument). Theparticles may either comprise the compound alone or in combination withsuitable other excipients that may aid the processing. The resultantfine particles may form the final formulation for delivery to humans ormay optionally be further formulated with other suitable excipients tofacilitate delivery in an acceptable dosage form.

The compounds of the invention may also be administered rectally, forexample in the form of suppositories or enemas, which include aqueous oroily solutions as well as suspensions and emulsions and foams. Suchcompositions are prepared following standard procedures, well known bythose skilled in the art. For example, suppositories can be prepared bymixing the active ingredient with a conventional suppository base suchas cocoa butter or other glycerides. In this case, the drug is mixedwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Such materials are cocoa butterand polyethylene glycols.

Generally, for compositions intended to be administered topically to theeye in the form of eye drops or eye ointments, the total amount of thecompound of the present invention will be about 0.0001 to less than 4.0%(w/w).

Preferably, for topical ocular administration, the compositionsadministered according to the present invention will be formulated assolutions, suspensions, emulsions and other dosage forms. Aqueoussolutions are generally preferred, based on ease of formulation, as wellas a patient's ability to administer such compositions easily by meansof instilling one to two drops of the solutions in the affected eyes.However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for compounds that are sparingly soluble inwater.

An alternative for administration to the eye is intravitreal injectionof a solution or suspension of the compound of the present invention. Inaddition, the compound of the present invention may also be introducedby means of ocular implants or inserts.

The compositions administered according to the present invention mayalso include various other ingredients, including, but not limited to,tonicity agents, buffers, surfactants, stabilizing polymer,preservatives, co-solvents and viscosity building agents. Suitablepharmaceutical compositions of the present invention include a compoundof the invention formulated with a tonicity agent and a buffer. Thepharmaceutical compositions of the present invention may furtheroptionally include a surfactant and/or a palliative agent and/or astabilizing polymer.

Various tonicity agents may be employed to adjust the tonicity of thecomposition, preferably to that of natural tears for ophthalmiccompositions. For example, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, simple sugars such as dextrose,fructose, galactose, and/or simply polyols such as the sugar alcoholsmannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, andhydrogenated starch hydrolysates may be added to the composition toapproximate physiological tonicity. Such an amount of tonicity agentwill vary, depending on the particular agent to be added. In general,however, the compositions will have a tonicity agent in an amountsufficient to cause the final composition to have an ophthalmicallyacceptable osmolality (generally about 150-450 mOsm, preferably 250-350mOsm and most preferably at approximately 290 mOsm). In general, thetonicity agents of the invention will be present in the range of 2 to 4%w/w. Preferred tonicity agents of the invention include the simplesugars or the sugar alcohols, such as D-mannitol.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate,sodium citrate, sodium borate or boric acid) may be added to thecompositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed.Preferably however, the buffer will be chosen to maintain a target pHwithin the range of pH 5 to 8, and more preferably to a target pH of pH5 to 7.

Surfactants may optionally be employed to deliver higher concentrationsof compound of the present invention. The surfactants function tosolubilise the compound and stabilise colloid dispersion, such asmicellar solution, microemulsion, emulsion and suspension. Examples ofsurfactants which may optionally be used include polysorbate, poloxamer,polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, andsorbitan monolaurate. Preferred surfactants to be employed in theinvention have a hydrophile/lipophile/balance “HLB” in the range of 12.4to 13.2 and are acceptable for ophthalmic use, such as TritonX114 andtyloxapol.

Additional agents that may be added to the ophthalmic compositions ofcompounds the present invention are demulcents which function as astabilising polymer. The stabilizing polymer should be an ionic/chargedexample with precedence for topical ocular use, more specifically, apolymer that carries negative charge on its surface that can exhibit azeta-potential of (−)10-50 mV for physical stability and capable ofmaking a dispersion in water (i.e. water soluble). A preferredstabilising polymer of the invention would be polyelectrolyte, orpolyelectrolytes if more than one, from the family of cross-linkedpolyacrylates, such as carbomers and Pemulen®, specifically Carbomer974p (polyacrylic acid), at 0.1-0.5% w/w.

Other compounds may also be added to the ophthalmic compositions ofcompounds of the present invention to increase the viscosity of thecarrier. Examples of viscosity enhancing agents include, but are notlimited to: polysaccharides, such as hyaluronic acid and its salts,chondroitin sulfate and its salts, dextrans, various polymers of thecellulose family; vinyl polymers; and acrylic acid polymers.

Topical ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben,phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1,or other agents known to those skilled in the art. Such preservativesare typically employed at a level of from 0.001 to 1.0% w/v. Unit closecompositions of the present invention will be sterile, but typicallyunpreserved. Such compositions, therefore, generally will not containpreservatives.

The medical practitioner, or other skilled person, will be able todetermine a suitable dosage for the compounds of the present invention,and hence the amount of the compound of the invention that should beincluded in any particular pharmaceutical formulation (whether in unitdosage form or otherwise).

A compound of formula (I) has therapeutic activity. Thus, in a furtheraspect, the present invention provides a compound as described hereinfor use in the treatment of one or more of the above mentionedconditions.

In a further aspect, the present invention provides use of a compound asdescribed herein for the manufacture of a medicament for the treatmentof one or more of the above mentioned conditions.

In a further aspect, the present invention provides a method oftreatment of one or more of the above mentioned conditions whichcomprises administering to a subject an effective amount of a compoundof the present invention or a pharmaceutical composition comprising thecompound.

The word “treatment” is intended to embrace prophylaxis as well astherapeutic treatment. Treatment of conditions or disorders alsoembraces treatment of exacerbations thereof.

A compound of the present invention may also be administered incombination with one or more other active ingredients e.g. activeingredients suitable for treating the above mentioned conditions.

For example, possible combinations for treatment of respiratorydisorders include combinations with steroids (e.g. budesonide,beclomethasone dipropionate, fluticasone propionate, mometasone furoate,fluticasone furoate, ciclesonide), beta agonists (e.g. terbutaline,salbutamol, salmeterol, formoterol, vilanterol, olodaterol, indacaterol,reproterol, fenoterol), xanthines (e.g. theophylline), anticholinergicsor muscarinic antagonists (e.g. ipratropium, tiotropium, aclidinium,umeclidinium or glycopyrronium for example as the bromide salt), PI3kinase inhibitors and anti-viral agents (e.g. zanamivir, oseltamivir,for example as the phosphate, peramivir and laninamivir).

In one embodiment there is provided a compound of the invention for useas a medicament to be administered in combination with one or morefurther active ingredients e.g. selected from corticosteroids, betaagonists, xanthines, muscarinic antagonists and PI3 kinase inhibitors.Suitably the beta agonist is a beta2 agonist.

In one embodiment the compound of the disclosure is administered byinhalation and a corticosteroid is administered orally or by inhalationeither in combination or separately.

In one embodiment the compound of the disclosure is administered byinhalation and a beta2 agonist is administered orally or by inhalationeither in combination or separately.

In one embodiment the compound of the disclosure is administered byinhalation and a muscarinic antagonist is administered orally or byinhalation either in combination or separately.

In one embodiment the compound of the disclosure is administered byinhalation either in combination or separately with one or more of acorticosteroid, a beta2 agonist and a muscarinic antagonist, alladministered either orally or by inhalation.

Further, for the treatment of gastrointestinal disorders (such asCrohn's disease or ulcerative colitis), possible combinations includecombinations with, for example, one or more agents selected from thelist comprising:

-   5-aminosalicylic acid, or a prodrug thereof (such as sulfasalazine,    olsalazine or bisalazide);-   corticosteroids (e.g. prednisolone, methylprednisolone, or    budesonide);-   immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate,    azathiopnne or 6-mercaptopurine);-   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab    pegol or golimumab);-   anti-IL12/IL23 antibodies (e.g. ustekinumab) or small molecule    IL12/IL23 inhibitors (e.g., apilimod);-   Anti-α4β7 antibodies (e.g. vedolizumab);-   MAdCAM-1 blockers (e.g. PF-00547659);-   antibodies against the cell adhesion molecule α4-integrin (e.g.    natalizumab);-   antibodies against the IL2 receptor a subunit (e.g. daclizumab or    basiliximab);-   JAK3 inhibitors (e.g. tofacitinib or R348);-   Syk inhibitors and prodrugs thereof (e.g. fostamatinib and R-406);-   Phosphodiesterase-4 inhibitors (e.g. tetomilast);-   HMPL-004;-   probiotics;-   Dersalazine;-   semapimod/CPSI-2364; and    -   protein kinase C inhibitors (e.g. AEB-071).

For the treatment of eye disorders (such as keratoconjunctivitis siccaor uveitis), possible combinations include combinations with, forexample, one or more agents selected from the list comprising:

-   -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   JAK3 inhibitors (e.g. tofacitinib or R348); and    -   protein kinase C inhibitors (e.g. AEB-071).

Hence another aspect of the invention provides a compound of formula (I)in combination with one or more further active ingredients, for exampleone or more active ingredients described above.

Similarly, another aspect of the invention provides a combinationproduct comprising:

(A) a compound of the present invention; and

(B) one or more other therapeutic agents,

wherein each of components (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier.

In this aspect of the invention, the combination product may be either asingle (combination) pharmaceutical formulation or a kit of parts.

Thus, this aspect of the invention encompasses a pharmaceuticalformulation including a compound of the present invention and anothertherapeutic agent, in admixture with a pharmaceutically acceptableadjuvant, diluent or carrier (which formulation is hereinafter referredto as a “combined preparation”).

It also encompasses a kit of parts comprising components:

-   (i) a pharmaceutical formulation including a compound of the present    invention in admixture with a pharmaceutically acceptable adjuvant,    diluent or carrier; and-   (ii) a pharmaceutical formulation including one or more other    therapeutic agents, in admixture with a pharmaceutically-acceptable    adjuvant, diluent or carrier,    which components (i) and (ii) are each provided in a form that is    suitable for administration in conjunction with the other.

Component (i) of the kit of parts is thus component (A) above inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier. Similarly, component (ii) is component (B) above in admixturewith a pharmaceutically acceptable adjuvant, diluent or carrier.

The one or more other therapeutic agents (i.e. component (B) above) maybe, for example, any of the agents mentioned above in connection withthe treatment of respiratory, gastrointestinal and eye disorders.

If component (B) is more than one further therapeutic agent, thesefurther therapeutic agents can be formulated with each other orformulated with component (A) or they may be formulated separately.

In one embodiment component (B) is one other therapeutic agent. Inanother embodiment component (B) is two other therapeutic agents.

The combination product (either a combined preparation or kit of parts)of this aspect of the invention may be used in the treatment orprevention of an inflammatory disease e.g. the inflammatory diseasesmentioned above, such as:

-   -   respiratory disorders including COPD (including chronic        bronchitis and emphysema), asthma, paediatric asthma, cystic        fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic        rhinitis, rhinitis and sinusitis, especially asthma, or COPD        (including chronic bronchitis and emphysema);    -   eye diseases or disorders including allergic conjunctivitis,        conjunctivitis, keratoconjunctivitis sicca (dry eye), glaucoma,        diabetic retinopathy, macular oedema (including diabetic macular        oedema), central retinal vein occlusion (CRVO), dry and/or wet        age related macular degeneration (AMD), post-operative cataract        inflammation or, particularly, uveitis (including posterior,        anterior and pan uveitis), corneal graft and limbal cell        transplant rejection;    -   skin diseases or disorders including allergic dermatitis,        contact dermatitis, atopic dermatitis or psoriasis; and    -   gastrointestinal diseases or disorders including gluten        sensitive enteropathy (coeliac disease), eosinophilic        esophagitis, intestinal graft versus host disease or,        particularly, ulcerative colitis or Crohn's disease.

The aspects of the invention described herein (e.g. the above-mentionedcompound, combinations, methods and uses) may have the advantage that,in the treatment of the conditions described herein, they may be moreconvenient for the physician and/or patient than, be more efficaciousthan, be less toxic than, be longer acting than, have better selectivityover, have a broader range of activity than, be more potent than,produce fewer side effects than, have a better pharmacokinetic and/orpharmacodynamic profile than, have more suitable solid state propertiesthan, have better stability than, or may have other usefulpharmacological properties over, similar compounds, combinations,methods (treatments) or uses known in the prior art for use in thetreatment of those conditions or otherwise.

Relative to compounds of the prior art, the compounds of formula (I) inat least some embodiments may additionally (or alternatively):

-   -   exhibit properties that are particularly suited to topical/local        administration (e.g. following topical/local administration, the        generation of high target tissue concentrations but low plasma        or systemic concentrations of the compounds of formula (I)        and/or rapid clearance of the compounds of formula (I) from        plasma or the systemic circulation);    -   have a reduced risk of extravascular exposure following        intravenous administration (e.g. due to a low volume of        distribution for the compounds of formula (I));    -   exhibit superior potency with respect to selected kinases and/or        a panel of kinases, such as p38 MAPKα, p38 MAPKγ, Src and        p59-HCK);    -   exhibit low or no inhibitory activity against Olaharsky kinases,        particularly GSK3α;    -   exhibit reduced β-catenin induction and/or inhibition of mitosis        in cells;    -   exhibit no or less time-dependent inhibition of members of the        cytochrome P450 superfamily; and/or    -   produce less problematic (e.g. less toxic) metabolites, e.g.        following administration to a patient.

EXPERIMENTAL SECTION

Abbreviations used herein are defined below (Table 1). Any abbreviationsnot defined are intended to convey their generally accepted meaning.

TABLE 1 Abbreviations AcOH glacial acetic acid Ac₂O acetic anhydride aqaqueous b broad BEH ethylene bridged hybrid BINAP1,1′-binaphthyl-2,2′-diamine Boc tert-butoxycarbonyl CSH charged surfacehybrid d doublet δ chemical shift DCM dichloromethane DIAD diisopropylazodicarboxylate DMF N,N-dimethylformamide DMSO dimethyl sulfoxide (ES⁺)electrospray ionization, positive mode (ES⁻) electrospray ionization,negative mode Et ethyl EtOAc ethyl acetate EtOH ethanol h hour(s) HATU1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate Hunig's N,N-diisopropylethylamine base IPAisopropyl alcohol ^(i)PrOAc isopropyl acetate m multiplet (M + H)⁺protonated molecular ion (M − H)⁻ deprotonated molecular ion Me methylMeCN acetonitrile MeOH methanol MHz megahertz min minute(s) m/zmass-to-charge ratio NMR nuclear magnetic resonance (spectroscopy)Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) Ph phenyl q quartetRT room temperature HPLC high performance liquid chromatography ssinglet sat saturated SCX solid supported cation exchange (resin) ttriplet ^(t)Bu tert-butyl THF tetrahydrofuran TFA trifluoroacetic acidUV ultra-violet AKT v-akt murine thymoma viral oncogene homolog 1 ATPadenosine-5′-triphosphate BALF bronchoalveolar lavage fluid BSA bovineserum albumin COPD chronic obstructive pulmonary disease CXCL1 chemokine(C-X-C motif) ligand 1 COX2 cytochrome c oxidase subunit II DSS dextransodium sulfate DTT dithiothreitol d-U937 PMA differentiated U-937 cellscells DVS dynamic vapour sorption dsRNA double stranded RNA ELISAenzyme-linked immunosorbent assay FACS fluorescence-activated cellsorting FBS foetal bovine serum FRET fluorescence resonance energytransfer GM-CSF CSF2: granulocyte-macrophage colony-stimulating factorGSK3α glycogen synthase kinase 3α GSK3β glycogen synthase kinase 3β HBSSHank's balanced salt solution HCK hemopoietic cell kinase HRV humanrhinovirus IBD inflammatory bowel disease IC50 50% inhibitoryconcentration ICAM-1 inter-cellular adhesion molecule 1 IFN interferonIL-2 interleukin 2 IL-8 interleukin 8 JNK c-Jun N-terminal kinase KCkeratinocyte chemoattractant LPMC lamina propria mononuclear cell LPSlipopolysaccharide MARK mitogen-activated protein kinase MAPKAP-K2mitogen-activated protein kinase-activated protein kinase-2 MKK4mitogen-activated protein kinase kinase 4 MKK6 mitogen-activated proteinkinase kinase 6 MOI multiplicity of infection MTT3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide OD opticaldensity PBMC peripheral blood mononuclear cell PBS Dulbecco's phosphatebuffered saline PHA phytohaemagglutinin PI3 phosphoinositide 3 kinasePMA phorbol 12-myristate 13-acetate REC50 relative 50% effectiveconcentration RNA ribonucleic acid RNAi RNA interference RT roomtemperature RSV respiratory syncytical virus SDS sodium dodecyl sulphateSRC v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)Syk spleen tyrosine kinase TCID50 50% tissue culture infectious doseTLR3 toll-like receptor 3 TNBS 2,4,6-trinitrobenzenesulphonic acid TNFαtumor necrosis factor alpha URTI Upper respiratory tract infection

CHEMISTRY EXAMPLES

General Procedures

All starting materials and solvents were obtained either from commercialsources or prepared according to the literature citation. Unlessotherwise stated all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate. Hydrogenations wereperformed on a Thales H-cube flow reactor under the conditions stated.

Column chromatography was performed on pre-packed silica (230-400 mesh,40-63 μm) cartridges using the amount indicated. SCX was purchased fromSupelco and treated with 1M hydrochloric acid prior to use. Unlessstated otherwise the reaction mixture to be purified was first dilutedwith MeOH and made acidic with a few drops of AcOH. This solution wasloaded directly onto the SCX and washed with MeOH. The desired materialwas then eluted by washing with 0.7 M NH₃ in MeOH.

Preparative Reverse Phase High Performance Liquid Chromatography

Performed using UV detection at 215 and 254 nm with either a WatersX-Select Prep-C18, 5 μm, 19×50 mm column eluting with a H₂O-MeCNgradient containing 0.1% v/v formic acid over 10 min, or a WatersX-Bridge Prep-C18, 5 μm, 19×50 mm column eluting with a H₂O-MeCNgradient containing 0.1% ammonium bicarbonate over 10 min.

Analytical Methods

Reverse Phase High Performance Liquid Chromatography

Method 1:

Waters XSelect CSH C18 2.5 μm (4.6×30 mm) at 40° C.; flow rate 2.5-4.5mL min⁻¹ eluted with a H₂O-MeCN gradient containing 0.1% v/v formic acidover 4 min employing UV detection at 254 nm. Gradient information:0-3.00 min, ramped from 95% H₂O-5% MeCN to 5% H₂O-95% MeCN; 3.00-3.01min, held at 5% H₂O-95% MeCN, flow rate increased to 4.5 mL min⁻¹;3.01-3.50 min, held at 5% H₂O-95% MeCN; 3.50-3.60 min, returned to 95%H₂O-5% MeCN, flow rate reduced to 3.50 mL min; 3.60-3.90 min, held at95% H₂O-5% MeCN; 3.90-4.00 min, held at 95% H₂O-5% MeCN, flow ratereduced to 2.5 mL min⁻¹.

Method 2:

Waters XBridge BEH C18, 2.5 μm (4.6×30 mm) at 40° C.; flow rate 2.5-4.5mL min⁻¹ eluted with a H₂O-MeCN gradient containing 10 mM ammoniumbicarbonate over 4 min employing UV detection at 254 nm. Gradientinformation: 0-3.00 min, ramped from 95% H₂O-5% MeCN to 5% H₂O-95% MeCN;3.00-3.01 min, held at 5% H₂O-95% MeCN, flow rate increased to 4.5 mLmin⁻¹; 3.01-3.50 min, held at 5% H₂O-95% MeCN; 3.50-3.60 min, returnedto 95% H₂O-5% MeCN, flow rate reduced to 3.50 mL min⁻¹; 3.60-3.90 min,held at 95% H₂O-5% MeCN; 3.90-4.00 min, held at 95% H₂O-5% MeCN, flowrate reduced to 2.5 mL min⁻¹.

¹H NMR Spectroscopy

¹H NMR spectra were acquired on a Bruker Avance III spectrometer at 400MHz using residual undeuterated solvent as reference and unlessspecified otherwise were run in DMSO-d₆.

COMPOUND EXAMPLES OF THE INVENTION Example 1:1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea Intermediate A:2-Chloro-4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridine

A mixture of (2-chloropyridin-4-yl)methanol (2.52 g, 17.6 mmol),4-nitronaphthalen-1-ol (3.01 g, 15.9 mmol) and PPh₃ (5.58 g, 21.3 mmol)was dissolved in THF (30 mL) under a nitrogen atmosphere and cooled in adry ice/acetone bath. DIAD (4.30 mL, 22.1 mmol) was added over 10 min tothe cooled stirred mixture which was then allowed to warm to ambienttemperature. After stirring for 19 h at ambient temperature MeOH (6 mL)was added and the mixture was evaporated in vacuo. Methanol (12 mL) wasadded to the resulting dark residue which was then sonicated for 20 min.The resulting solid was collected by filtration and washed with MeOH (50mL) and ether (50 mL) to afford a dark yellow gum. The crude materialwas purified by silica gel chromatography (80 g, gradient 0-50% EtOAc iniso-hexane) to yield the subtitle compound2-chloro-4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridine as a yellowsolid. (2.66 g, 48%); R^(t) 2.50 min (Method 1); m/z 315 (M+H)⁺ (ES⁺);¹H NMR δ: 5.58 (2H, s), 7.18 (1H, d), 7.62 (1H, m), 7.70 (1H, bs), 7.76(1H, m), 7.87 (1H, m), 8.45-8.49 (3H, overlapping m), 8.59 (1H, d).

Intermediate B:N-(4-(((4-Nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)pyrazin-2-amine

A mixture of 2-chloro-4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridine(Intermediate A) (308 mg, 0.88 mmol), 2-aminopyrazine (125 mg, 1.31mmol), BINAP (110 mg, 0.18 mmol) and cesium carbonate (556 mg, 1.71mmol) in 1,4-dioxane was purged under a nitrogen atmosphere for 10 min.Pd₂(dba)₃ (77 mg, 0.08 mmol) was added and the mixture was purged withnitrogen for a further 10 min and then heated to 90° C. After stirringfor 19 h at 90° C. the reaction mixture was cooled to ambienttemperature and partitioned between EtOAc (50 mL) and water (50 mL). Thelayers were separated and the organic phase was washed with water (2×50mL), brine (2×50 mL) and then dried (MgSO₄), filtered and concentratedin vacuo to afford the crude product as an orange solid. The solid wastriturated with MeOH (20 mL) and washed with MeOH (2×20 mL) to yield thesubtitle compoundN-(4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)pyrazin-2-amineas an orange solid (156 mg, 36%); R^(t) 1.69 min (Method 1); m/z 374(M+H)⁺ (ES⁺).

Intermediate C:N-(4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)pyrazin-2-amine

A solution ofN-(4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)pyrazin-2-amine(Intermediate B) (156 mg, 0.32 mmol) in a mixture of DCM (10 mL) andMeOH (1 mL) was passed through a Thales H-cube (10% Pt/C, 30×4 mm, Fullhydrogen, 40° C., 1 mL/min). The volatiles were removed in vacuo toyield the subtitle compoundN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)pyrazin-2-amineas a tan solid (121 mg, 88%); R^(t) 0.81 min (Method 1); m/z 344 (M+H)⁺(ES⁺).

Intermediate D: 3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine

To a stirred solution of p-tolylhydrazine hydrochloride (100 g, 630mmol) in EtOH (1251 mL) was added 4,4-dimethyl-3-oxopentanenitrile (88g, 699 mmol) and HCl (62.5 mL, 750 mmol). The resulting mixture wasstirred at reflux overnight. The reaction mixture was cooled to roomtemperature and concentrated in vacuo to c.a. ⅓ of the original volume.The reaction mixture was then cooled in an ice-bath and taken to c.a. pH8-9 with 6M aq NaOH. The reaction mixture was extracted with diethylether (500 mL) and the organic phase washed with water (2×300 mL) beforebeing dried over magnesium sulphate and concentrated in vacuo to affordan orange solid. The solid was suspended in iso-hexane and stirred atreflux for 2.5 h before being cooled and filtered whilst still hot toyield the subtitle product 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine asa pale brown solid (76.5 g, 52%); R^(t) 1.31 min (Method 1); m/z 230(M+H)⁺ (ES⁺); ¹H NMR δ: 1.20 (9H, s), 2.32 (3H, s), 5.10 (2H, br s),5.35 (1H, s), 7.24 (2H, d), 7.42 (2H, m).

Intermediate E: Phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate

A solution of 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine(Intermediate D) (20 g, 87.0 mmol) in isopropyl acetate (240 mL) wasadded to a stirred solution of sodium carbonate (11.3 g, 106 mmol) inwater (80 mL). After 10 min phenyl chloroformate (12.1 mL, 96 mmol) wasadded and the resulting mixture was stirred at ambient temperatureovernight. The reaction mixture was diluted with water (160 mL), thelayers were separated and the organics were washed with water (2×80 mL),brine (80 mL), dried (MgSO₄) and concentrated in vacuo. The resultingyellow solid was suspended in 10% ether/iso-hexane (320 mL) and stirreduntil a uniform suspension was obtained. The solid was collected byfiltration and washed with iso-hexane to yield the subtitle compoundphenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate as a whitepowder (27.3 g, 88%); R^(t) 2.65 min (Method 1); m/z 350 (M+H)⁺ (ES⁺);¹H NMR δ: 1.29 (9H, s), 2.37 (3H, s), 6.35 (1H, s), 7.10-7.23 (3H,overlapping m), 7.33-7.46 (6H, overlapping m), 9.99 (1H, s).

Intermediate F: tert-Butyl(4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate

To a mixture of 2-chloro-4-(chloromethyl)pyridine (30 g, 185 mmol) andtert-butyl (4-hydroxynaphthalen-1-yl)carbamate (40.0 g, 154 mmol) inacetonitrile (200 mL) was added caesium carbonate (75 g, 231 mmol) andthe resulting mixture was heated to 55° C. After 16 h the reactionmixture was diluted with 30% MeOH in DCM (600 mL) and water (400 mL).The layers were separated and the aqueous layer was extracted with afurther amount of 30% MeOH in DCM (2×600 mL) and the organics wereconcentrated in vacuo to afford the crude product. The crude product wastriturated with MeOH (200 mL), sonicated for c.a. 5 min and slurried for1 day. The resulting solid was collected by filtration and washed withMeOH (2×10 mL) to yield the subtitle compoundtert-butyl(4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate asa yellow solid (43 g, 70%); R^(t) 2.60 min (Method 1); m/z 383 (M−H)⁻(ES⁻); ¹H NMR δ: 1.47 (9H, s), 5.41 (2H, s), 6.98 (1H, d), 7.36 (1H, d),7.55-7.61 (3H, overlapping m), 7.65 (1H, m), 7.94 (1H, m), 8.29 (1H, m),8.45 (1H, m), 9.00 (1H, bs).

Intermediate C (Protected):tert-Butyl(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate

The following procedure was carried out twice: a suspension oftert-butyl (4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(Intermediate F) (10.0 g, 25.5 mmol), 2-aminopyrazine (7.27 g, 76.0mmol) and caesium carbonate (16.6 g, 50.9 mmol) in 1,4-dioxane (100 mL)was purged with nitrogen for 10 min. Pd₂(dba)₃ (1.17 g, 1.27 mmol) andBINAP (1.59 g, 2.55 mmol) in 1,4-dioxane (40 mL) was added and theresulting mixture was heated to 90° C. After 6.5 h both reactionmixtures were allowed to cool to ambient temperature, combined, dilutedwith 10% MeOH in DCM (300 mL) and filtered through a plug of Celite. TheCelite pad was washed with 10% MeOH in DCM (300 mL), the solvents wereconcentrated in vacuo and the residue was dissolved in MeOH (200 mL) andstirred at ambient temperature for 2 h. The resulting solid wascollected by filtration and washed with MeOH (20 mL) and diethyl ether(20 mL) to afford the impure product as bright orange solid. The crudematerial was combined, slurried in a mixture of MeOH (200 mL) and EtOH(200 mL) for 16 h. The solids were collected by filtration and dried(94% purity). The solid was treated with MeOH (200 mL) and EtOH (200 mL)and slurried for a further 16 h. The solids were collected by filtrationand washed with iso-hexane (2×100 mL) to yield the subtitle compoundtert-butyl(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamateas a tan solid (13.7 g, 60%); R^(t) 2.4 min (Method 2); m/z 444 (M+H)⁺(ES⁺); ¹H NMR δ: 1.47 (9H, s), 5.36 (2H, s), 7.01 (1H, d), 7.07 (1H, m),7.36 (1H, d), 7.57-7.62 (2H, overlapping m), 7.95 (1H, m), 8.01 (1H,bs), 8.09 (1H, m), 8.22 (1H, m), 8.29 (1H, m), 8.38 (1H, m), 8.99 (1H,bs), 9.08 (1H, m), 10.2 (1H, s).

Intermediate C (alternative method):N-(4-(((4-Aminonaphthalen-1-yl)oxy)methyl) pyridin-2-yl)pyrazin-2-amine

To a suspension oftert-butyl(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(Intermediate C (protected)) (13.9 g, 31.3 mmol) in DCM (140 mL) atambient temperature was added TFA (24 mL) and the resulting solution wasstirred at ambient temperature. After 3 h the solvent was removed invacuo and the residue was poured onto sat. aq. NaHCO₃ (500 mL). Theresulting mixture was sonicated for 2 min, slurried for 16 h and theresulting precipitate was collected by filtration and washed with water(300 mL) and acetonitrile (100 mL) to yield the subtitle compoundN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)pyrazin-2-amineas a tan solid, partial TFA salt (10 g, 92%); R^(t) 1.9 min (Method 2);m/z 344 (M+H)⁺ (ES⁺); ¹H NMR δ: 5.20 (2H, s), 5.23 (2H, s), 6.60 (1H,d), 6.84 (1H, d), 7.06 (1H, m), 7.43-7.51 (2H, overlapping m), 7.98 (1H,s), 8.05 (1H, d), 8.08 (1H, m), 8.22 (1H, m), 8.25-8.29 (2H, overlappingm), 9.07 (1H, m), 10.1 (1H, s).

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea

To a mixture of phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate E)(14.1 g, 40.4 mmol) andN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)pyrazin-2-amine(Intermediate C) (10 g, 28.8 mmol) in isopropyl acetate (400 mL) heatedto 40° C. was added triethylamine (0.804 mL, 5.77 mmol). The resultingmixture was stirred for 1 h and then cooled to ambient temperature andstirred for a further 16 h. The excess solvents were removed in vacuoand the residue was dissolved in 20% MeOH in DCM (1000 mL) and washedwith sat. aq. NaHCO₃ (300 mL). The aqueous layer was extracted with afurther amount of 20% MeOH in DCM (200 mL) and the combined organicswere washed with brine (200 mL) and concentrated in vacuo. The materialobtained was combined with acetonitrile (200 mL) and slurried for 5 h.The resulting mixture was warmed to 50° C. and allowed to cool toambient temperature (cycle repeated twice) and the solid was collectedby filtration to afford a grey lumpy solid. The material was recombinedwith acetonitrile (700 mL), warmed to 50° C. for 30 min, cooled toambient temperature, stirred for 3 h and filtered. The solid wasrecombined with acetonitrile (300 mL) and slurried for a further 72 h.The resulting solid was collected by filtration to yield the titlecompound1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaas a beige solid (14 g, 80%); R^(t) 1.97 min (Method 1); m/z 599 (M+H)⁺(ES⁺); ¹H NMR δ: 1.27 (9H, s), 2.39 (3H, s), 5.35 (2H, s), 6.36 (1H, s),7.04 (1H, d), 7.08 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.59-7.66 (3H,overlapping m), 7.95 (1H, m), 8.01 (1H, bs), 8.09 (1H, d), 821 (1H, m),8.30 (1H, d), 8.40 (1H, m), 8.59 (1H, s), 8.80 (1H, s), 9.08 (1H, d),10.15 (1H, s).

Example 2:1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaIntermediate G (Protected): tert-Butyl(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate

A mixture oftert-butyl(4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(Intermediate F) (1050 mg, 2.73 mmol), 6-ethylpyrazin-2-amine (437 mg,3.55 mmol), and cesium carbonate (1333 mg, 4.09 mmol) in 1,4-dioxane (15mL) was degassed with nitrogen for 5 min. A solution of Pd₂(dba)₃ (125mg, 0.136 mmol) and BINAP (170 mg, 0273 mmol) in 1,4-dioxane (5 mL) wasadded, and the reaction mixture stirred at 90° C. for 6 h. The reactionmixture was allowed to cool and was stirred at room temperature for 16h, then diluted with 10% MeOH/DCM (25 mL) and filtered through a plug ofCelite, washing with additional 10% MeOH/DCM (15 mL). The solvent wasremoved in vacuo and the crude product was combined with MeOH (15 mL)and slurried for 3 h. The resulting orange solid was isolated byfiltration, then combined with MeOH/EtOH (5 mL) solution and stirred for72 h. Again the resulting orange solid was isolated by filtration, thenacetone (20 mL) was added and the mixture was slurried for 2 h. Theresidual solid was filtered off, and the filtrate was evaporated to givethe subtitle compoundtert-butyl(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(360 mg, 27%); R^(t) 2.6 min (Method 2); m/z 472 (M+H)⁺ (ES⁺); ¹H NMR δ:1.18 (3H, t), 1.47 (9H, s), 2.63 (2H, q), 5.36 (2H, s), 6.99 (1H, d),7.06 (1H, d), 7.36 (1H, d), 7.53-7.63 (2H, m), 7.90-8.06 (3H,overlapping m), 8.29 (1H, d), 8.36 (1H, m), 8.91 (1H, s), 8.96 (1H, s),10.06 (1H, s).

Intermediate G:N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine

TFA (1.485 mL, 19.09 mmol) was added to a solution oftert-butyl(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(Intermediate G (protected)) (360 mg, 0.763 mmol) in DCM (15 mL), andthe reaction mixture stirred at room temperature for 4 h, thenconcentrated in vacuo. The residue was combined with sat. sodiumhydrogencarbonate solution and stirred at room temperature for 16 h. Thesolid was filtered, washing with acetonitrile, and dried under vacuum togive the subtitle compoundN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amineas a beige solid (200 mg, 69%); R^(t) 2.14 min (Method 2); m/z 372(M+H)⁺ (ES⁺); ¹H NMR δ: 1.20 (3H, t), 2.64 (2H, q), 5.18-5.24 (4H,overlapping m), 6.59 (1H, d), 6.82 (1H, d), 7.03 (1H, d), 7.41-7.51 (2H,overlapping m), 7.98-8.01 (2H, m), 8.04 (1H, m), 8.22-8.29 (2H,overlapping m), 8.91 (1H, s), 10.04 (1H, s).

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1)urea

Triethylamine (0.013 mL, 0.093 mmol) was added to a solution ofphenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate(Intermediate E) (0.042 g, 0.121 mmol) andN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine(Intermediate G) (0.093 g, 0.250 mmol) in THF (1.5 mL) at 40° C. Thereaction mixture was stirred at 40° C. for 40 min then cooled to RT andstirred for 3 days, and then concentrated in vacuo. The crude productwas purified by silica gel chromatography (12 g column, 0 to 5% MeOH inDCM) to give an off white-brown solid. The product was re-purified bypreparative HPLC (Gilson, Acidic (0.1% Formic acid), Acidic, WatersX-Select Prep-C18, 5 μm, 19×50 mm column, 45-75% MeCN in water) toafford the title compound1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaas an off white solid (0.029 g, 49%); R^(t) 2.26 min (Method 1); m/z 627(M+H)⁺ (ES⁺), 625 (M−H)⁻ (ES⁻); ¹H NMR δ: 1.18 (3H, t), 1.28 (9H, s),2.40 (3H, s), 2.63 (2H, q), 5.36 (2H, s), 6.36 (1H, s), 7.02 (1H, d),7.07 (1H, dd), 7.37 (2H, m), 7.45 (2H, m), 7.56-7.67 (3H, overlappingm), 7.94 (1H, m), 7.99 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.39 (1H,m), 8.60 (1H, s), 8.81 (1H, s), 8.92 (1H, s), 10.08 (1H, s).

Example 2A:1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea(free base and maleate) Intermediate G(i): tert-butylN-[4-[(2-chloro-4-pyridyl)methoxy]-1-naphthyl]carbamate

Acetonitrile (420 mL) was added to 2-chloro-4-(chloromethyl)pyridine(59.5 g) (1.05 eq), and the mixture stirred at 20° C. tert-Butyl(4-hydroxynaphthalen-1-yl)carbamate (90.8 g) was added to the mixturethen potassium carbonate (72.6 g) was added. The heterogeneous mixturewas warmed to 55° C. at a rate of 1.0 K/min.

The mixture was stirred for 16 h at 55° C. then the reaction mixture wascooled to 22° C. Water (1260 mL) was added over 30 min and the mixturewas stirred for 30 min at 22° C.

The precipitate was filtered and washed with water (2×200 mL). Theproduct was dried in vacuo at 50° C. for 20 h to give tert-butylN-[4-[(2-chloro-4-pyridyl)methoxy]-1-naphthyl]carbamate (100.0 g,90.6%).

Intermediate G(II) (Protected): tert-butyl(4-((2-(6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate

1,4-Dioxane (125 mL) was added totert-butyl-N-[4-[(2-chloro-4-pyridyl)methoxy]-1-naphthyl]carbamate(Intermediate G(i)) (9.6 g) and the mixture stirred at 20° C. Cesiumcarbonate (16.3 g) (2 eq) and 2-amino-6-ethylpyrazine (4.8 g) (1.5 eq)were added to the stirred mixture at 20° C. Argon was purged through thereaction mixture. Tris(dibenzylideneacetone)dipalladium(0) (1.14 g)(0.05 eq) and racemic BINAP (1.56 g) (0.10 eq) were added to thereaction mixture. The mixture was stirred for an additional 15 min at20° C. The mixture was heated to 90° C. at a rate of 1.5 K/min, thenstirred for 12 h at 90° C. The mixture was cooled to 20° C. and stirringcontinued for an additional 6 h. The heterogeneous mixture was filteredover Celite, and the filter washed with 1,4-dioxane (twice 5 mL). Thefiltrate was concentrated in vacuo at 20 mbar and 50° C. The residue wasdissolved in ethanol (150 mL). Spontaneous crystallisation occurred. Theheterogeneous mixture was stirred for 3 h at 22° C. The precipitate wasfiltered and washed with ethanol (10 mL). The product was dried in vacuoat 50° C. for 20 h to givetert-butyl(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(9.05 g, 76.8%).

Intermediate G(II):N-[4-[(4-amino-1-naphthyl)oxymethyl]-2-pyridyl]6-ethyl-pyrazin-2-amine

Acetonitrile (200 mL) was added totert-butyl-N-[4-[[2-[(6-ethylpyrazin-2-yl)amino]-4-pyridyl]methoxy]-1-naphthyl]carbamate(Intermediate D (protected)) (10.5 g) and the heterogeneous mixturestirred at 20° C. Sulfuric acid (5.5 mL) (4.5 eq) was added over 2 h at20° C. The heterogeneous mixture was stirred for an additional 2 h at20° C. Aqueous ammonia (17 mL) (10 eq) was added to the reaction mixtureover 15 min, keeping the temperature at 20° C. by cooling. Water (33.4mL) was added to the heterogeneous mixture over 5 min at 20° C. Afterstirring for 30 min at 20° C., the mixture was cooled to 5° C. andstirred for an additional 2 h at 5° C. The precipitate was filtered andwashed with water (33.4 mL) and 2-propanol (18 mL). The product wasdried at 50° C. in vacuo for 24 h to giveN-[4-[(4-amino-1-naphthyl)oxymethyl]-2-pyridyl]-6-ethyl-pyrazin-2-amine(6.2 g, 75%).

1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea

2-methyltetrahydrofuran (1809 mL) was added toN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine(Intermediate D) (41.3 g) and the mixture was stirred at 20° C. Phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (51.3 g) (1.2 eq)was added to the mixture. Triethylamine (3.9 mL) (0.25 eq) was added andthe mixture stirred for an additional 10 min at 20° C. The heterogeneousreaction mixture was warmed to 48° C. over 30 min and kept at 48° C. for3.5 h. After 10 min at 48° C., the mixture became homogeneous, and wasseeded with crystalline1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea(60 mg). The reaction mixture was allowed to cool to 20° C. and stirredfor an additional 16 h. The formed precipitate was filtered and washedwith 2-methyltetrahydrofuran (twice 139 mL). The product was dried for18 h at 45° C. in vacuo to give1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea(54.1 g, 77.5%).

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureamaleate (Form 2)

2-Butanone (4442 mL) was added to1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea(111.04 g) and stirred at 20° C. The heterogeneous mixture was warmed to65° C. and became a homogeneous solution. SilicaMetS Thiol (metalscavenger) (5.55 g) was added and the mixture stirred for 30 min at 65°C. Norit A Supra (activated charcoal) (5.55 g) added and the mixturestirred for an additional 20 min at 65° C. The mixture was filtered warmover Celite. The filter was washed with warm (60° C.) 2-butanone (1555mL). 2-Butanone (2887 mL) was added to the filtrate and brought to 60°C. while stirring.

Maleic acid (20.56 g) (1.0 eq) was dissolved in 2-butanone (555 mL). Themaleic acid solution was added to the1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureasolution over 80 min at 65° C. After 10% of the maleic acid solution isadded, the mixture was seeded with crystalline1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea maleate Form 2. The mixturewas kept stirring for 1 h at 60° C., then cooled non-linearly with anexponent of 2.3 over 6 h to 5° C. The precipitate was filtered andwashed twice with 2-butanone (278 mL). The product was dried at 45° C.in vacuo for 20 h to give1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureamaleate Form 2 (113.8 g, 86.5%).

The powder XRD pattern (CuKα radiation) of a sample of this materialshowed diffraction peaks at 4.2, 8.4, 8.7, 11.0, 11.5, 12.6, 14.4, 14.9,16.0, 17.0, 17.4, 18.8, 19.5, 20.2, 21.7, 22.4, 23.8, 25.8 and 26.3(±0.2) degrees 2-theta without the presence of a halo, indicating thatthe compound is present as a crystalline product (Form 2 polymorph).

Example 2B:1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureamaleate (Form 2) (Different Batch)

2-Butanone (750 mL) was added to1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea(7.50 g) and the mixture was stirred. The mixture was warmed to 60° C.over 20 min. A solution of maleic acid (1.39 g) in 2-butanone (12 mL)was added to the mixture over 5 min. Spontaneous crystallisationoccurred after approximately half of the maleic acid solution was added.The mixture was stirred for 30 min at 60° C. then cooled to 5° C. over 6h with an exponential ramp (exponent=2.3) then stirred for 30 min at 5°C. then heated to 65° C. over 30 min then stirred for 30 min at 65° C.then cooled to 5° C. over 6 h with an exponential ramp (exponent=2.3)then stirred for 30 min at 5° C. then heated to 65° C. over 30 min thenstirred for 30 min at 65° C. then cooled to 5° C. over 6 h with anexponential ramp (exponent=2.3). The product was filtered and washedtwice with 2-butanone (50 mL), subsequently dried at 45° C. in vacuo togive1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureamaleate (Form 2) (7.0 g).

Example 2C:1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureamaleate (Form 1)

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureamaleate (15 mg) was dissolved in THF (100 vol.) at 50° C. andtemperature cycled between 50° C. and room temperature over 24 h (4 h ateach temperature). The solution was then kept in the fridge for 24 hafter which the solid material (Form 1) was isolated.

Example 2D: 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol5-yl)-3-(4-((2-(6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureamaleate (Form 1) (Different Batch)

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureawas dissolved in THF (40 vol.) at 50° C. and 1 equivalent of maleic acidwas added. The sample was left to mature between RT and 50° C. (4 h ateach temperature) for 2 days. Solid material (Form 1) was isolated.

The powder XRD pattern (CuKα radiation) of a sample of this materialshowed diffraction peaks at 3.8, 6.3, 7.8, 9.3, 9.9, 10.7, 11.2, 12.7,15.4, 16.5, 17.9, 19.2 and 19.6 (±0.2) degrees without the presence of ahalo, indicating that the compound is present as a crystalline product(Form 1 polymorph).

Example 3:5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamideIntermediate H: 4-(((4-Nitronaphthalen-1-yl)oxy)methyl)pyridin-2-amine

4-Nitronaphthalen-1-ol (60 g, 317 mmol), (2-aminopyridin-4-yl)methanol(44.6 g, 359 mmol) and triphenylphosphine (120 g, 458 mmol) weredissolved in tetrahydrofuran (616 mL, 7516 mmol) and cooled in a dryice/acetone bath. (E)-Diisopropyl diazene-1,2-dicarboxylate (89 mL, 458mmol) was added drop-wise over 20 min. The reaction mixture was allowedto warm to RT and was left to stir overnight. The reaction mixture wasdiluted with MeOH (80 mL) and concentrated to a black gel. The gel wastaken up in MeOH (430 mL), sonicated for 40 min and stirred at roomtemperature for 3 h. The solid was collected via vacuum filtration,washing with MeOH (300 mL), to afford the subtitle compound4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-amine as a black-yellowsolid (28 g, 27%); R^(t) 1.31 min (Method 1); m/z 296 (M+H)⁺ (ES⁺).

Intermediate I: 5-Chloro-N-(2-methoxyethyl)pyrazine-2-carboxamide

Oxalyl chloride (0.974 mL, 11.35 mmol) and few drops of DMF were addedto a suspension of 5-chloropyrazine-2-carboxylic acid (1.5 g, 9.46mmol), in dichloromethane (20 mL) and the reaction mixture was stirredfor 2 h at room temperature under an atmosphere of nitrogen. Thereaction mixture was concentrated in vacuo and dissolved indichloromethane (10 mL) and cooled to 0° C. 2-methoxyethanamine (0.905mL, 10.41 mmol) was then added dropwise to the solution, followed byHunig's base (1.756 mL, 10.41 mmol). The reaction mixture was stirredovernight at room temperature, before being partitioned between waterand dichloromethane, The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by silica gelchromatography (40 g column, iso-hexane-ethyl acetate 0-50%) to affordthe subtitle compound 5-chloro-N-(2-methoxyethyl)pyrazine-2-carboxamideas colourless solid (1.67 g, 78%); R^(t) 1.86 min (Method 1); m/z 216(M+H)⁺ (ES⁺).

Intermediate J:N-(2-Methoxyethyl)-5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide

4-(((4-Nitronaphthalen-1-yl)oxy)methyl)pyridin-2-amine (Intermediate H)(2.410 g, 8.16 mmol), 5-chloro-N-(2-methoxyethyl)pyrazine-2-carboxamide(Intermediate I) (1.6 g, 7.42 mmol), Pd₂(dba)₃ (0.340 g, 0.371 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.462 g, 0.742 mmol) andcesium carbonate (3.63 g, 11.13 mmol) were flushed with nitrogen andsuspended in 1,4-dioxane (35 mL). The resultant mixture was degassedwith nitrogen for 10 min and the dark brown mixture heated at 90° C. for15 h. The crude mixture was cooled and then diluted with 10% MeOH/DCM(10 mL) and filtered through Celite, washing with further 10% MeOH/DCM(50 mL). The solvent was removed to yield the crude as a dark brownresidue. This was triturated with methanol and filtered to afford thesubtitle compoundN-(2-methoxyethyl)-5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide as a brown solid (3 g, 75%); R^(t) 1.93 min(Method 1); m/z 475 (M+H)⁺ (ES⁺).

Intermediate K:5-((4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide

To a stirred solution ofN-(2-methoxyethyl)-5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide(Intermediate J) (1 g, 2.108 mmol) in THF (25 mL), a few drops of aceticacid were added and the resulting mixture was degassed for 10 min withnitrogen. Pt/C (0.1 g) was then added. The resulting mixture was stirredunder hydrogen at 5 bar overnight. The suspension was filtered throughCelite, and the solvent removed in vacuo to yield the crude as darkbrown residue. This was dissolved in a mixture of MeOH/DCM/THF andabsorbed onto SCX, washed with MeOH and released with 1% NH₃ in MeOH.The 1% NH₃ in MeOH fraction was concentrated under reduced pressure toafford the subtitle compound5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamideas a brown solid (0.7 g, 61%); R^(t) 1.13 min (Method 1); m/z 445 (M+H)⁺(ES⁺).

5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide

Phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate(Intermediate E) (259 mg, 0.742 mmol) was added to a solution of5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide(Intermediate K) (300 mg, 0.675 mmol), in tetrahydrofuran (6 mL). Thereaction mixture was heated to 40° C. and triethylamine (0.033 mL, 0.240mmol) was then added. The reaction mixture was left to heat at 40° C.for 1 h then allowed to cool to room temperature and left to stirovernight. Methanol (3 mL) was added and the product was collected byfiltration to afford the title compound5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)pyrazine-2-carboxamide(120 mg, 25%); R^(t) 1.88 min (Method 1); m/z 700 (M+H)⁺ (ES⁺); ¹H NMRδ: 1.28 (9H, s), 2.40 (3H, s), 328 (3H, s), 3.43-3.49 (4H, m), 5.39 (2H,s), 6.35 (1H, s), 7.05 (1H, d), 7.17 (1H, m), 7.37 (2H, m), 7.46 (2H,m), 7.58-7.68 (3H, overlapping m), 7.95 (1H, m), 8.10 (1H, s), 8.34 (1H,d), 8.41 (1H, d), 8.47 (1H, m), 8.59 (1H, s), 8.75 (1H, s), 8.94 (1H,s), 9.06 (1H, s), 10.61 (1H, s).

Example 4:1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaIntermediate L (Protected): tert-Butyl(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate

The reaction was carried out on an identical scale twice:—

Cesium carbonate (1323 g, 40.6 mmol) was added to a suspension oftert-butyl(4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(Intermediate F) (10.42 g, 27.1 mmol), 5,6-dimethylpyrazin-2-amine (5 g,40.6 mmol), Pd₂(dba)₃ (1.239 g, 1.353 mmol) and BINAP (1.685 g, 2.71mmol) in 1,4-dioxane (100 mL) at room temperature under nitrogen. Thesuspension was sonicated for 5 min and degassed with nitrogen for 10 minbefore being stirred at 90° C. overnight. The reaction mixture wascooled to room temperature and diluted with a solution of 10% MeOH inDCM (500 mL) before being filtered through a pad of Celite, washing withadditional 10% MeOH in DCM (100 mL). The filtrate was concentrated invacuo. At this stage the two identical reactions were combined. Thecombined residues were suspended in MeOH (125 mL) before being stirredfor 16 h. The solid was collected via filtration. The residue wasslurried in MeOH (100 mL) for 2 h and the solid filtered (3×). Thematerial was slurried in a 1:1 mixture of 10% MeOH in DCM/EtOH (100 mL)for 1 hr twice, filtered and dried. The solid was dried overnight toafford the subtitle compoundtert-butyl(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate)as a beige solid (13.3 g, 51%); R^(t) 2.56 min (Method 2); m/z 472(M+H)⁺ (ES⁺).

Intermediate L:N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-5,6-dimethylpyrazin-2-amine

Trifluoroacetic acid (41.8 mL, 543 mmol) was added to a stirringsolution oftert-butyl(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(Intermediate L (protected)) (132 g, 27.2 mmol) in dichloromethane (608mL). The reaction was stirred at room temperature for 2 h. The reactionmixture was concentrated under reduced pressure, and DCM (100 mL) wasadded to the residue, and solvent once again removed in vacuo. Theresidue was slurried in NaHCO₃ solution (700 mL), sonicated and stirredfor 1 h and the solid was filtered off. The solid was washed with water(300 mL) and dried under vacuum for 16 h to give the subtitle compoundN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-5,6-dimethylpyrazin-2-amineas an off-white solid (9.33 g, 92%); R^(t) 2.0 min (Method 2); m/z 372(M+H)⁺ (ES⁺).

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea

Phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate(Intermediate E) (6.95 g, 19.69 mmol), was added to a solution ofN-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-5,6-dimethylpyrazin-2-amine(Intermediate L) (7 g, 17.90 mmol) in tetrahydrofuran (150 mL), Thereaction mixture was heated to 40° C. and triethylamine (0.886 mL, 6.36mmol) was added. The reaction mixture was left to heat at 40° C. for 1 hthen allowed to cool to room temperature and left to stir overnight. Thereaction mixture was diluted with 20% MeOH in DCM solution (250 mL) andthe mixture was washed with saturated aqueous sodium hydrogencarbonatesolution (200 mL) and water (300 mL), and the organic layer combinedwith silica (25 g) and the solvent was evaporated. The crude product waspurified first by silica gel chromatography (2×220 g Hi loading Sicolumn, 0-5% MeOH in DCM), and secondly by slurrying in acetone (200 mL)for 16 h. The solid obtained was collected by filtration and dried undervacuum to give the title compound1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaas a white solid (5.2 g, 46%); R^(t) 2.60 min (Method 2); m/z 627 (M+H)⁺(ES⁺); ¹H NMR δ: 1.28 (9H, s), 2.37 (3H, s), 2.39 (3H, s), 2.40 (3H, s),5.34 (2H, s), 6.37 (1H, s), 6.99-7.06 (2H, overlapping m), 7.37 (2H, m),7.45 (2H, m), 7.58-7.67 (3H, overlapping m), 7.88 (1H, s), 7.94 (1H, m),8.27 (1H, d), 8.41 (1H, m), 8.60 (1H, s), 8.80 (1H, s), 8.89 (1H, s),9.90 (1H, s).

Example 5:1-(4-((2-((5-(Aminomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureaIntermediate M: tert-Butyl ((5-chloropyrazin-2-yl)methyl)carbamate

(5-chloropyrazin-2-yl)methanamine hydrochloride (0.100 g, 0.555 mmol)was suspended in isopropyl alcohol (1.0 mL, 12.98 mmol). Triethylamine(0.100 mL, 0.717 mmol) and then di-tert-butyl dicarbonate (0.160 mL,0.689 mmol) ware added. The resulting mixture was stirred at roomtemperature for 2 h, then 1,4-dioxane (1 mL) was added, followed byfurther triethylamine (0.100 mL, 0.717 mmol) and THF (2 mL). After atotal of 5 h, the reaction mixture was concentrated under reducedpressure to afford the crude product as a brown solid, which waspurified by silica gel chromatography (12 g column, iso-hexane-ethylacetate 0-50%) to give the subtitle compoundtert-butyl((5-chloropyrazin-2-yl)methyl)carbamate as a white solid (106mg, 77%); R^(t) 1.76 min (Method 1); m/z 143 (M+H-Boc)⁺ (ES⁺), m/z 188(M+H-^(t)Bu)⁺ (ES⁺).

Intermediate N: tert-Butyl((5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamate

4-(((4-Nitronaphthalen-1-yl)oxy)methyl)pyridin-2-amine (Intermediate H)(0.129 g, 0.419 mmol), tert-butyl((5-chloropyrazin-2-yl)methyl)carbamate(Intermediate M) (0.106 g, 0.426 mmol), cesium carbonate (0.218 g, 0.669mmol), BINAP (0.033 g, 0.053 mmol) and Pd₂(dba)₃ (0.020 g, 0.022 mmol)were suspended in 1,4-dioxane (3.2 mL). The reaction mixture wasdegassed with nitrogen for 15 min and then stirred at 90° C. for 24 h.The reaction mixture was allowed to cool, then diluted with 10% MeOH inDCM (25 mL), and filtered through Celite, washing through with 10% MeOHin DCM (2×25 mL). The combined filtrate was concentrated under reducedpressure to afford a dark residue, which was triturated with MeOH. Thesolid obtained was filtered and washed with MeOH (2×20 mL), thenpurified by silica gel chromatography (12 g column, 10% MeOH in DCM-DCM0-50%) to give the subtitle compoundtert-butyl((5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamateas a yellow solid (91 mg, 32%); R^(t) 1.97 min (Method 1); m/z 503(M+H)⁺ (ES⁺), 501 (M−H)⁻ (ES⁻).

Intermediate O: tert-Butyl((5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamate

tert-Butyl((5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamate (Intermediate N) (0.091 g, 0.136 mmol) was dissolved in 10%MeOH in DCM (10.0 mL). The reaction mixture was hydrogenated in theH-Cube (10% Pt/C, 30×4 mm, Full hydrogen, 40° C., 1 mL/min). Thereaction mixture was reduced in volume under reduced pressure and thenabsorbed onto SCX, washed with MeOH and released with 1% NH₃ in MeOH.The 1% NH₃ in MeOH fraction was concentrated under reduced pressure toafford the subtitle compoundtert-butyl((5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamateas a yellow glassy solid (53 mg, 74%); R^(t) 1.26 min (Method 1); m/z473 (M+H)⁺ (ES⁺), 471 (M−H)⁻ (ES⁻).

Intermediate P: tert-Butyl((5-((((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamate

tert-Butyl((5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamate(Intermediate O) (0.053 g, 0.101 mmol) and phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate E)(0.041 g, 0.116 mmol) were dissolved in THF (1.0 mL). The reactionmixture was heated to 40° C. and then triethylamine (0.005 mL, 0.036mmol) was added. The reaction mixture was left to heat at 40° C. for 1 hthen allowed to cool to room temperature and left to stir overnight.After a total of 21.5 h the reaction mixture was diluted with MeOH (2mL), evaporated onto silica and purified by silica gel chromatography(12 g column, 10% MeOH in DCM-DCM 0-50%) to give the subtitle compoundtert-butyl((5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamateas a pale tan solid (54 mg, 66%); R^(t) 2.19 min (Method 1); m/z 728(M+H)⁺ (ES⁺), 726 (M−H)⁻ (ES⁻).

1-(4-((2-((5-(Aminomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

TFA (0200 mL, 2.60 mmol) was added to a solution of tert-butyl((5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)carbamate(Intermediate P) (0.054 g, 0.067 mmol) in DCM (1.0 mL). The resultingsolution was stirred at room temperature for 2.5 h, then the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in MeOH, absorbed onto SCX, washed with MeOH and released with1% NH₃ in MeOH. The 1% NH₃ in MeOH fraction was concentrated underreduced pressure to afford the crude product as a yellow solid. This waspurified by silica gel chromatography (4 g column, 10% (1% NH₃ in MeOH)in DCM-DCM 0-100%) to give the title compound1-(4-((2-((5-(aminomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureaas a pale yellow solid (20 mg, 45%); R^(t) 1.57 min (Method 1); m/z 628(M+H)⁺ (ES⁺), 626 (M−H)⁻ (ES⁻); ¹H NMR δ: 1.27 (9H, s), 2.39 (3H, s),3.77 (2H, s), 5.34 (2H, s), 6.36 (1H, s), 7.00-7.07 (2H, overlapping m),7.34 (2H, m), 7.44 (2H, m), 7.59-7.67 (3H, overlapping m), 7.93-7.95(2H, overlapping m), 8.25-8.30 (2H, overlapping m), 8.40 (1H, m), 8.59(1H, s), 8.80 (1H, s), 9.03 (1H, d), 10.04 (1H, s).

Example 6:N-(5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)acetamide

Acetic anhydride (0.005 mL, 0.053 mmol) was added to a mixture of1-(4-((2-((5-(aminomethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(Example 5) (0.017 g, 0.026 mmol) and triethylamine (0.010 mL, 0.072mmol) in DCM (1.0 mL). The reaction mixture was stirred at roomtemperature for 90 min and then concentrated under reduced pressure. Theresidue was dissolved in MeOH/DCM and absorbed onto SCX, washed withMeOH and released with 1% NH₃ in MeOH. The 1% NH₃ in MeOH fraction wasconcentrated under reduced pressure to afford the title productN-((5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methyl)acetamide as a pale yellowsolid (15 mg, 84%); R^(t) 1.81 min (Method 1); m/z 670 (M+H)⁺ (ES⁺), 668(M−H)⁻ (ES⁻); ¹H NMR δ: 1.28 (9H, s), 1.89 (3H, s), 2.40 (3H, s), 4.30(2H, d), 5.35 (2H, s), 6.37 (1H, s), 7.01-7.10 (2H, overlapping m), 7.37(2H, m), 7.44 (2H m), 7.60-7.67 (3H, overlapping m), 7.93 (1H, dd), 8.00(1H, s), 8.16 (1H, d), 8.29 (1H, m), 8.42 (2H, overlapping m), 8.60 (1H,s), 8.81 (1H, s), 9.03 (1H, d), 10.13 (1H, s).

Example 7:5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-methylpyrazine-2-carboxamideIntermediate Q: Methyl5-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate

A solution of Pd₂(dba)₃ (0299 g, 0.327 mmol),2-chloro-4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridine (IntermediateA), methyl 5-aminopyrazine-2-carboxylate (1.00 g, 6.53 mmol), BINAP(0.407 g, 0.653 mmol) and cesium carbonate (3.19 g, 9.80 mmol) in1,4-dioxane (20 mL) was degassed with nitrogen for 10 min and thenheated to 90° C. for 16 h. The reaction mixture was cooled, diluted withMeOH (30 mL) and the suspension was filtered through a Celite pad,washing with 1% NH₃ in MeOH (100 mL). The filtrate was concentratedunder reduced pressure. The residue was suspended in DCM (20 mL), MeOH(100 mL) and the resulting solid was captured and rinsed with MeOH (50mL) and hexane (50 mL) to give the subtitle compound methyl5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate(0.58 g, 18%); R^(t) 2.09 min (Method 1); m/z 432 (M+H)⁺ (ES⁺).

Intermediate R: Methyl5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate

Wet Pt/C (0.267 g, 0.065 mmol) was added to a solution of methyl5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate(Intermediate Q) (0.557 g, 1.291 mmol) in THF (20 mL) and AcOH (3drops). The reaction mixture was stirred under 5 bar hydrogen for 5 h.The reaction was diluted with MeOH (20 mL) and filtered through a Celitepad, washing with MeOH (20 mL). The combined filtrate was concentratedunder reduced pressure to give the subtitle compound methyl5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate(0.28 g, 35%); R^(t) 1.16 min (Method 1); m/z 402 (M+H)⁺ (ES⁺).

Intermediate S:5-((4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicadd hydrochloride

Lithium hydroxide (0.034 g, 1.420 mmol) was added to a solution ofmethyl5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate(Intermediate R) (0.228 g, 0.568 mmol) in THF:Water (10 mL:3 mL) and thereaction mixture heated at 40° C. for 3 h, then concentrated underreduced pressure. To the residue was added 1M HCl (10 mL) and thesuspension was filtered, washing with water (10 mL) and diethyl ether(10 mL). A brown hydroscopic solid was obtained, which was dissolved inMeOH (30 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure to give the subtitle compound5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid hydrochloride as a dark brown solid (0.208 g, 82%); R^(t) 0.97 min(Method 1); m/z 388 (M+H)⁺ (ES⁺).

Intermediate T:5-((4-(((4-(3-(3-tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid

Triethylamine (0.374 mL, 2.68 mmol) was added to a solution of phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate E)(0.281 g, 0.805 mmol) and5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid hydrochloride (Intermediate S) (0.208 g, 0.491 mmol) in THF (10 mL)and the reaction mixture stirred at 40° C. for 5 h. The reaction wasconcentrated under reduced pressure and the residue was triturated withDCM (10 mL) and diethyl ether (20 mL). The resulting suspension wasfiltered, washing with diethyl ether (20 mL), to give the subtitlecompound5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid (0.215 g, 56%); R^(t) 2.08 min (Method 1); m/z 643 (M+H)⁺ (ES⁺).

5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-methylpyrazine-2-carboxamide

Hunig's Base (0.109 mL, 0.622 mmol) was added to a stirring solution of5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid (Intermediate T) (0.080 g, 0.124 mmol), HATU (0.062 g, 0.162 mmol)and methylamine hydrochloride (0.042 g, 0.622 mmol) in DCM (3 mL). Thereaction mixture was stirred at 40° C. for 16 h. Water (10 mL) was addedand the solution sonicated, before a solid was collected by filtration.The crude product was purified by preparative HPLC (Gilson, Basic (0.1%Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mmcolumn, 25-70% MeCN in water) to afford the title compound5-((4-(((4-(3-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-methylpyrazine-2-carboxamideas a pale brown solid (3 mg, 3.6%); R^(t) 2.17 min (Method 1); m/z 656(M+H)⁺ (ES⁺); ¹H NMR δ: 1.28 (9H, s), 2.40 (3H, s), 2.83 (3H, d), 5.39(2H, s), 6.36 (1H, s), 7.05 (1H, d), 7.16 (1H, d), 7.38 (2H, m), 7.44(2H, m), 7.59-7.66 (3H, overlapping m), 7.95 (1H, m), 8.10 (1H, s), 8.36(1H, s), 8.41 (1H, m), 8.54 (1H, q), 8.65 (1H, br s), 8.75 (1H, d), 8.85(1H, s), 9.05 (1H, s), 10.57 (1H, s).

Example 8:2-(6-(4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-methylacetamideIntermediate U: Methyl 2-(6-chloropyrazin-2-yl)acetate

To an ice-cold solution (0-4° C.) of 2-(6-chloropyrazin-2-yl)acetic acid(0.6 g, 3.48 mmol) in MeOH (7 mL) was added thionyl chloride (0.508 mL,6.95 mmol) dropwise. The resulting solution was allowed to warm to roomtemperature and stirred for 2 h. The reaction mixture was concentratedin vacuo and the solid residue was dissolved in EtOAc (50 mL) andtreated with sat. aq. NaHCO₃ (50 mL). The layers ware separated and theorganic phase dried over MgSO₄, then filtered and concentrated in vacuoto afford the subtitle compound methyl 2-(6-chloropyrazin-2-yl)acetateas a yellow oil (0.647 g, 95%); R^(t) 1.21 min (Method 1); m/z 187(M+H)⁺ (ES⁺).

Intermediate V: Methyl2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetate

A flask was charged with4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-amine (Intermediate H)(1 g, 3.39 mmol), methyl 2-(6-chloropyrazin-2-yl)acetate (IntermediateU) (0.632 g, 3.39 mmol), BINAP (0.211 g, 0.339 mmol), cesium carbonate(1.655 g, 5.08 mmol) and Pd₂(dba)₃ (0.155 g, 0.169 mmol). To this wasadded 1,4-dioxane (25 mL) and the resulting mixture was purged withnitrogen for 5 min and then heated to 90° C. for 2 h. The reactionmixture was cooled to room temperature and taken up in a mixture of 10%MeOH in DCM and passed through a Celite pad and concentrated in vacuo toafford a brown semi solid. This was triturated with MeOH (10 mL) toafford the subtitle compound methyl2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetateas a brown solid (856 mg, 53%); R^(t) 1.83 min (Method 1); m/z 446(M+H)⁺ (ES⁺).

Intermediate W:2-(6-((4-(((4-Nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)aceticacid

A solution of LiOH (0.056 g, 2.357 mmol) in water (1.8 mL) was added toa solution of methyl2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetate(Intermediate V) (0.7 g, 1.572 mmol) in THF (6 mL). The resultingmixture was heated to 40° C. for 2 h and then stirred at roomtemperature for a further 1 h. The reaction mixture was concentrated invacuo and the residue was treated with 1M aq HCl to afford a tancoloured precipitate. This was collected under vacuum filtration,washing with water (2×5 mL), to afford the subtitle compound2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)aceticacid as a tan coloured solid (682 mg, 89%); R^(t) 1.60 min (Method 1);m/z 432 (M+H)⁺ (ES⁺).

Intermediate X:N,N-Dimethyl-2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetamide

To a stirred solution of2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)aceticadd (Intermediate W) (0.151 g, 0.350 mmol) in DCM (5 mL) was addeddimethylamine hydrochloride (0.143 g, 1.750 mmol) and Hunig's base(0.306 mL, 1.750 mmol), followed by HATU (0.200 g, 0.525 mmol), and theresulting mixture was stirred at room temperature overnight. Thereaction mixture was treated with 1M HCl, the layers separated, and theorganic phase was washed with sat. aq. NaHCO₃ (10 mL) and brine (2×20mL), and passed through a phase sep. cartridge to afford a brown viscousoil after solvent evaporation. The oil was purified by silica gelchromatography (12 g column, 0-5% MeOH in DCM) to afford the subtitlecompoundN,N-dimethyl-2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetamideas a yellow solid (64 mg, 38%); R^(t) 1.61 min (Method 1); m/z 459(M+H)⁺ (ES⁺), 457 (M−H)⁻ (ES⁻).

Intermediate Y:2-(6-((4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-dimethylacetamide

Platinum/C paste (25.5 mg, 0.013 mmol) was added to a solution ofN,N-dimethyl-2-(6-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)acetamide(Intermediate X) (60 mg, 0.131 mmol) in THF (5 mL) with a drop of AcOH.The resulting mixture was stirred under an atmosphere of hydrogen at 5bar for 5 h. The reaction mixture was passed through a pad of Celite andconcentrated in vacuo to afford a brown glass. The crude product wasloaded onto a column of SCX (2 g) in MeOH. The column was washed withMeOH and then the product was eluted with 0.7M ammonia in MeOH. Theresultant mixture was concentrated in vacuo to afford the subtitlecompound2-(6-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-dimethylacetamideas a brown glass (56 mg, 80%); R^(t) 0.95 min (Method 1); m/z 429 (M+H)⁺(ES⁺).

2-(6-((4-(((4-(3-(3-(tert-Butyl)-1(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-dimethylacetamide

To a stirred solution of2-(6-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-dimethylacetamide(Intermediate Y) (50 mg, 0.093 mmol) and phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate E)(42.4 mg, 0.121 mmol) in THF (1.5 mL) was added triethylamine (13.01 μl,0.093 mmol). The resulting mixture was heated to 40° C. for 3 h, thenquenched with MeOH and concentrated in vacuo to give a pink solid. Thiswas triturated with MeOH (2 mL) to afford the title compound2-(6-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-N,N-dimethylacetamideas pale pink solid (22 mg, 33.8%); R^(t) 1.88 min (Method 1); m/z 684(M+H)⁺ (ES⁺); ¹H NMR δ:1.27 (9H, s), 2.39 (3H, s), 2.81 (3H, s), 3.00(3H, s), 3.78 (2H, s), 5.33 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.07(1H, dd), 7.36 (2H, d), 7.44 (2H, m), 7.56-7.61 (2H, overlapping m),7.64 (1H, d), 7.88 (1H, s), 7.93 (1H, m), 7.99 (1H, s), 8.30 (1H, m),8.36 (1H, m), 8.58 (1H, s), 8.79 (1H, s), 9.03 (1H, s), 10.10 (1H, s).

Example 9:5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-dimethylpyrazine-2-carboxamideIntermediate Z:5-((4-((4-Nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid

Lithium hydroxide (0.024 g, 0.985 mmol) was added to a solution ofmethyl5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate(Intermediate Q) (0.085 g, 0.197 mmol) in THF/Water (5 mL, 1:1). Thereaction mixture was heated at 40° C. for 16 h, then concentrated underreduced pressure. Water (2 mL) was added to the residue and the aqueouswas made acidic with 1M aq HCl (2 mL), giving a precipitate, which wasisolated by filtration, to give the subtitle compound5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid as a pale tan solid (80 mg, 88%); R^(t) 1.85 min (Method 1); m/z418 (M+H)⁺ (ES⁺).

Intermediate AA:N,N-Dimethyl-5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide

Hunig's base (0.335 mL, 1.917 mmol) was added to a stirring solution of5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid (Intermediate Z) (0.08 g, 0.192 mmol), HATU (0.095 g, 0.249 mmol)and dimethylamine hydrochloride (0.156 g, 1.917 mmol) in DCM (5 mL) andthe reaction mixture stirred for 16 h. The reaction was concentratedunder reduced pressure and water (20 mL) was added to the residue. Theresulting suspension was filtered to give the subtitle compoundN,N-dimethyl-5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamideas a brown solid (80 mg, 85%); R^(t) 1.78 min (Method 1); m/z 445 (M+H)⁺(ES⁺), 443 (M−H)⁻ (ES⁻).

Intermediate BB:5-((4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-dimethylpyrazine-2-carboxamide

Pt/C (3.73 mg, 0.018 mmol) was added to a solution ofN,N-dimethyl-5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide(Intermediate AA) (0.08 g, 0.180 mmol) in THF (5 mL) and AcOH (1 drop)under a atmosphere of nitrogen. The reaction mixture was then stirredunder an atmosphere of 1 bar hydrogen at room temperature for 24 h. Thereaction was filtered through Celite and rinsed with MeOH (20 mL) andDCM (20 mL). The filtrate was concentrated under reduced pressure andthe residue was diluted with MeOH (5 mL) and loaded onto a SCXcartridge. The cartridge was rinsed with MeOH (3 column volumes) andproduct eluted with 1% NH₃ MeOH (3 column volumes). The ammonia/methanolsolution was concentrated under reduced pressure to give the subtitlecompound5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-dimethylpyrazine-2-carboxamide (22 mg, 22%); R^(t) 1.01 min (Method1); m/z 415 (M+H)⁺ (ES⁺).

5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-dimethylpyrazine-2-carboxamide

Triethylamine (8.32 μl, 0.060 mmol) was added to a stirring solution ofphenyl (3-(tert-butyl) 1-(p-tolyl)-1H-pyrazol-5-yl)carbamate(Intermediate E) (0.021 g, 0.060 mmol) and5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-dimethylpyrazine-2-carboxamide(Intermediate BB) (0.022 g, 0.040 mmol) in DCM (5 mL) and the reactionmixture was stirred at 40° C. for 16 h. The reaction mixture wasconcentrated under reduced pressure and loaded onto a silica pad and thecrude product was purified by chromatography on silica gel (12 g column,gradient 0-5% MeOH in DCM) to afford the title compound5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N,N-dimethylpyrazine-2-carboxamideas a pale tan solid (7 mg, 24%); R^(t) 2.03 min (Method 1); m/z 670(M+H)⁺ (ES⁺); ¹H NMR δ: 1.28 (9H, s), 2.40 (3H, s), 3.02 (3H, s), 3.10(3H, s), 5.38 (2H, s), 6.36 (1H, s), 7.05 (1H, d), 7.14 (1H, d), 7.37(2H, m), 7.44 (2H, m), 7.59-7.66 (3H, overlapping m), 7.94 (1H, m), 8.01(1H, s), 8.35 (1H, d), 8.41 (1H, m), 8.47 (1H, d), 8.59 (1H, s), 8.80(1H, s), 9.08 (1H, s), 10.47 (1H, s).

Example 10:1-(3-(tert-Butyl)-1-p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaIntermediate CC:(5-((4-(((4-Nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methanol

A mixture of 2-chloro-4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridine(Intermediate A) (0.265 g, 0.842 mmol), (5-aminopyrazin-2-yl)methanol(0.105 g, 0.842 mmol), BINAP (0.052 g, 0.084 mmol), cesium carbonate(0.412 g, 1.263 mmol) and Pd₂(dba)₃ (0.039 g, 0.042 mmol) in 1,4-dioxane(6 mL) was purged with nitrogen for 10 min, then kept under a nitrogenatmosphere and heated to 90° C. for 2 h. The reaction mixture was cooledto room temperature, diluted with 10% MeOH in DCM (100 mL), and passedthrough a pad of Celite, washing with further 10% MeOH in DCM (2×30 mL).The filtrate was concentrated in vacuo and triturated with MeOH (10 mL)to afford the subtitle compound(5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methanolas a burnt orange solid (274 mg, 77%); R^(t) 1.57 min (Method 1); m/z404 (M+H)⁺ (ES⁺).

Intermediate DD:(5-((4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methanol

(5-((4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methanol(Intermediate CC) (0.27 g, 0.669 mmol) was taken up in 5% AcOH in THF(15 mL) and the reaction mixture was hydrogenated in the H-Cube (10%Pt/C, 30×4 mm, Full hydrogen, ambient temp, 1 mL/min; 2 passes). Thereaction mixture was then concentrated in vacuo to give a purple solid.The crude product was loaded onto a column of SCX (4 g) in 5% AcOH inMeOH/DCM. The column was washed with MeOH (2×10 mL) and then the productwas eluted with 0.7M ammonia in MeOH (2×20 mL). The product fractionswere concentrated in vacuo to afford the subtitle compound(5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methanolas a dark purple solid (150 mg, 33%); R^(t) 1.70 min (Method 1); m/z 374(M+H)⁺ (ES⁺).

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea

Triethylamine (0.024 mL, 0.175 mmol) was added to a solution of(5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)methanol(Intermediate DD) (119 mg, 0.175 mmol) and phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate E)(80 mg, 0.228 mmol) in THF (2.5 mL). The resulting mixture was heated to40° C. for 2 h. The reaction mixture was cooled to room temperature,quenched with MeOH (2 mL) and concentrated in vacuo to afford a darkpurple solid. This was taken up in a mixture of MeOH/DCM, concentratedonto silica and was purified by silica gel chromatography (12 g column,0-5% MeOH in DCM) to afford the title compound1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaas a pink solid (19 mg, 16%); R^(t) 1.79 min (Method 1); m/z 629 (M+H)⁺(ES⁺); ¹H NMR δ: 1.27 (9H, s), 2.39 (3H, s), 4.54 (2H, d), 5.35 (1H, s),5.37 (2H, t), 6.36 (1H, s), 6.99-7.12 (2H, overlapping m), 7.36 (2H, d),7.44 (2H, d), 7.56-7.70 (3H, overlapping m), 7.93 (1H, m), 7.97 (1H, s),8.26 (1H, d), 8.29 (1H, dd), 8.40 (1H, m), 8.58 (1H, s), 8.79 (1H, s),9.03 (1H, s), 10.09 (1H, s).

Examples 11-52

The following examples were prepared using methods analogous to thosedescribed above for the preparation of Examples 1-10:

Example 11:

R^(t) 1.17 min (Method 1); m/z 624 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 5.39 (2H, s), 6.35 (1H, s), 7.05(1H, d), 7.18 (1H, dd), 7.36 (2H, m), 7.45 (2H, m), 7.57-7.66 (3H,overlapping m), 7.89- 7.96 (2H, overlapping m), 8.35-8.42 (2H,overlapping m), 8.60-8.65 (2H, overlapping m), 8.83 (1H, s), 9.35 (1H,s), 10.70 (1H, s). Route code*: 3 Example 12:

R^(t) 1.77 min (Method 1); m/z 616 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ 1.27 (9H, s), 3.94 (3H, s), 5.35 (2H, s), 6.37 (1H, s),6.97-7.05 (2H, overlapping m), 7.08 (1H, dd), 7.57-7.67 (3H, overlappingm), 7.84-7.94 (2H, overlapping m), 8.01 (1H, s), 8.09 (1H, d), 8.22 (1H,dd), 8.30 (1H, dd), 8.35- 8.42 (2H, overlapping m), 8.64 (1H, s), 8.76(1H, s), 9.08 (1H, d), 10.16 (1H, s). Route code*: 3 Example 13:

R^(t) 1.96 min (Method 1); m/z 605 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ 1.26 (9H, s), 2.49 (3H, d), 5.37 (2H, s), 6.35 (1H, s), 6.82(1H, m), 7.04, (1H, d), 7.05 (1H, d), 7.10 (1H, dd), 7.607.70 (3H,overlapping m), 7.97-8.04 (2H, overlapping m), 8.10 (1H, d), 8.23 (1H,dd), 8.31 (1H, dd), 8.41 (1H, m), 8.67 (1H, s), 8.94 (1H, s), 9.09 (1H,d), 10.17 (1H, s). Route code*: 3 Example 14:

R^(t) 2.6 min (Method 2); m/z 642 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 2.97 (6H, s), 5.33 (2H, s), 6.35(1H, s), 6.99 (1H, d), 7.03 (1H, m), 7.36 (2H, m), 7.44 (2H, m),7.54-7.64 (4H, overlapping m), 7.93 (1H, m), 8.07 (1H, s), 8.11 (1H, s),8.26 (1H, d), 8.31 (1H, m), 8.57 (1H, s), 8.78 (1H, s), 9.65 (1H, s).Route code*: 1 Example 15:

R^(t) 2.73 min (Method 2); m/z 639 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 0.85-0.94 (4H, overlapping m), 1.27 (9H, s), 1.98-2.06 (1H,m), 2.39 (3H, s), 5.34 (2H, s), 6.35 (1H, s), 6.99 (1H, d), 7.07 (1H,dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, overlapping m),7.89-7.95 (2H, overlapping m), 8.03 (1H, s), 8.28 (1H, d), 8.36 (1H, m),8.58 (1H, s), 8.77- 8.80 (2H, overlapping m), 9.94 (1H, s). Route code*:1 Example 16:

R^(t) 2.11 min (Method 1); m/z 639 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 0.85 (2H, m), 0.94 (2H, m), 1.27 (9H, s), 2.10 (1H, ddd),2.39 (3H, s), 5.33 (2H, s), 6.36 (1H, s), 6.97-7.08 (2H, overlapping m),7.36 (2H, m), 7.44 (2H, m), 7.56-7.67 (3H, overlapping m), 7.86 (1H, s),7.93 (1H, m), 8.17 (1H, d), 8.25 (1H, dd), 8.38 (1H, m), 8.58 (1H, s),8.79 (1H, s), 8.96 (1H, d), 9.93 (1H, s). Route code*: 3 Example 17:

R^(t) 1.68 min (Method 1): m/z 755 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 2.42-2.40 (7H, over- lapping m), 3.40-3.35(4H, overlapping m), 3.58 (4H, t), 5.39 (2H, s), 6.36 (1H, s), 7.05 (1H,d), 7.17 (1H, d), 7.37 (2H, m), 7.46 (2H, m), 7.59-7.66 (3H, overlappingm), 7.95 (1H, m), 8.10 (1H, s), 8.35 (1H, d), 8.41 (1H, m), 8.46 (1H,t), 8.64 (1H, s), 8.76 (1H, d), 8.85 (1H, d), 9.06 (1H, d), 10.59 (1H,s). Route code*: 4 Example 18:

R^(t) 2.36 min (Method 1); m/z 629 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.29 (9H, s), 2.40 (3H, s), 3.80 (3H, s), 5.37 (2H, s), 6.36(1H, s), 7.01 (1H, d), 7.10 (1H, d), 7.38 (2H, m), 7.44 (2H, m), 7.58-7.64 (3H, overlapping m), 7.33 (1H, s), 7.92-9.95 (2H, over- lapping m),8.32 (1H, d), 8.35 (1H, m), 8.59 (1H, s), 8.63 (1H, s), 8.80 (1H, s),10.06 (1H, s). Route code*: 1 Example 19:

R^(t) 2.03 min (Method 1); m/z 613 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 2.40 (3H, s), 5.34 (2H, s), 6.35(1H, s), 7.01-7.05 (2H, over- lapping m), 7.36 (2H, m), 7.44 (2H, m),7.58-7.65 (3H, over- lapping m), 7.89 (1H, s), 7.93 (1H, m), 8.11 (1H,s), 8.27 (1H, d), 8.39 (1H, m), 8.61 (1H, s), 8.81 (1H, s), 9.02 (1H,s), 9.97 (1H, s). Route code*: 1 Example 20:

R^(t) 2.10 min (Method 1); m/z 613 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.35 (3H, s), 2.39 (3H, s), 5.35 (2H, s), 6.36(1H, s), 7.01-7.06 (2H, overlapping m), 7.36 (2H, m), 7.43 (2H, m),7.57-7.67 (3H, overlapping m), 7.93 (1H, m), 7.98 (2H, s), 8.29 (1H, d),8.41 (1H, m), 8.60 (1H, s), 8.81 (1H, s), 8.94 (1H, s), 10.10 (1H, s).Route code*: 1 Example 21:

R^(t) 1.82 min (Method 1); m/z 629 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ 1.27 (9H, s), 2.39 (3H, s), 4.53 (2H, d), 5.35 (2H, s), 5.48(1H, s), 6.36 (1H, s), 7.03 (1H, d), 7.06 (1H, m), 7.36 (2H, d), 7.45(2H, m), 7.59-7.68 (3H, overlapping m), 7.91-7.98 (2H, overlapping m),8.16 (1H, s), 8.29 (1H, d), 8.40 (1H, m), 8.58 (1H, s), 8.79 (1H, s),9.01 (1H, s), 10.13 (1H, s). Route code*: 2 Example 22:

R^(t) 2.25 min (Method 1); m/z 655 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 0.85-0.93 (4H, overlapping m), 1.26 (9H, s), 2.02 (1H, m),3.83 (3H, s), 5.34 (2H, s), 6.33 (1H, s), 6.99 (1H, d), 7.05-7.12 (3H,overlapping m), 7.45 (2H, m), 7.55-7.64 (3H, overlapping m), 7.90-7.93(2H, overlapping m), 8.03 (1H, s), 8.28 (1H, d), 8.36 (1H, m), 8.52 (1H,br s), 8.77 (1H, br s), 8.78 (1H, br s), 9.94 (1H, br s). Route code*: 1Example 23:

R^(t) 1.72 min ( Method 1); m/z 645 (M + H)⁺ (ES⁺); 643 (M − H)⁻ (ES⁻);¹H NMR (400 MHz, DMSO-d₆) δ: 1.26 (9H, s), 3.83 (3H, s), 4.54 (2H, s),5.30-5.42 (3H, over- lapping m), 6.34 (1H, s), 7.01-7.13 (4H,overlapping m), 7.45 (2H, m), 7.59-7.66 (3H, overlapping m), 7.93 (1H,m), 7.97 (1H, br s), 8.26 (1H, s), 8.29 (1H, d), 8.40 (1H, m), 8.53 (1H,br s), 8.79 (1H, br s), 9.02 (1H, br s), 10.10 (1H, br s). Route code*:1 Example 24:

R^(t) 2.39 min (Method 1); m/z 645 (M + H)⁺ (ES⁺); 643 (M − H)⁻ (ES⁻);¹H NMR (400 MHz, DMSO-d₆) δ: 0.85-0.95 (4H, overlapping m), 1.25 (9H,s), 2.02 (1H, m), 2.48 (3H, s), 5.35 (2H, s), 6.33 (1H, s), 6.81 (1H,m), 6.99-7.08 (3H, over- lapping m), 7.56-7.66 (3H, overlapping m), 7.92(1H, s), 7.98 (1H, d), 8.03 (1H, s), 8.29 (1H, d), 8.37 (1H, d), 8.64(1H, br s), 8.78 (1H, br s), 8.92 (1H, br s), 9.94 (1H, br s). Routecode*: 1 Example 25:

R^(t) 2.01 min (Method 1); m/z 655 (M + H)⁺ (ES⁺); 653 (M − H)⁻ (ES⁻);¹H NMR (400 MHz, DMSO-d₆) δ: 0.85-0.94 (4H, overlapping m), 1.27 (9H,s), 2.02 (1H, m), 4.59 (2H, d), 5.30-5.36 (3H, overlapping m), 6.36 (1H,s), 6.99 (1H, d), 7.07 (1H, d), 7.46-7.53 (4H, over- lapping m),7.55-7.64 (3H, overlapping m), 7.91-7.95 (2H, overlapping m), 8.03 (1H,s), 8.28 (1H, d), 8.36 (1H, d), 8.61 (1H, s), 8.78 (1H, br s), 8.79 (1H,br s), 9.94 (1H, br s). Route code*: 1 with compound (II) protectedthrough the process and deprotected as a final step Example 26:

R^(t) 1.82 min (Method 1): m/z 635 (M + H)⁺ (ES⁺); 633 (M − H)⁻ (ES⁻);¹H NMR (400 MHz, DMSO-d₆) δ: 1.25 (9H, s), 2.48 (3H, br s), 4.54 (2H,s), 5.36 (3H, s), 6.34 (1H, s), 6.82 (1H, d), 7.02-7.08 (3H, overlappingm), 7.59-7.68 (3H, over- lapping m), 7.96-8.02 (2H, overlapping m), 8.26(1H, s), 8.29 (1H, d), 8.41 (1H, m), 8.65 (1H, br s), 8.93 (1H, br s),9.02 (1H, br s), 10.10 (1H, br s). Route code*: 1 Example 27:

R^(t) 2.36 min (Method 1); m/z 645 (M + H)⁺ (ES⁺); 643 (M − H)⁻ (ES⁻);¹H NMR (400 MHz, DMSO-d₆) δ: 0.85-0.95 (4H, overlapping m), 1.25 (9H,s), 2.02 (1H, m), 5.35 (2H, s), 6.31 (1H, s), 7.00 (1H, d), 7.06-7.08(2H, overlapping m), 7.39 (1H, d), 7.56-7.65 (3H, overlapping m), 7.92(1H, s), 7.99 (1H, d), 8.03 (1H, s), 8.29 (1H, d), 8.37 (1H, d), 8.60(1H, br s), 8.78 (1H, br s), 8.86 (1H, br s), 9.94 (1H, br s). MissingCH₃ resonance presumed 2.50 ppm obscured by residual DMSO peak 2.49-2.51ppm. Route code*: 1 Example 28:

R^(t) 1.82 min (Method 1); m/z 670 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 2.60 (3H, d), 3.55 (2H, s), 5.33(2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.07 (2H, overlapping dd), 7.36(2H, m), 7.44 (2H, m), 7.60 (1H, m), 7.64 (1H, d), 7.84 (1H, s), 7.93(1H, m), 8.01 (1H, m), 8.03 (1H, s), 8.29 (1H, d), 8.38 (1H, m), 8.58(1H, s), 8.79 (1H, s), 9.09 (1H, s), 10.12 (1H, s). Route code*: 5Example 29:

R^(t) 1.88 min (Method 1); m/z 684 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 2.81 (3H, s), 3.00 (3H, s),3.78 (2H, s), 5.33 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.07 (2H, dd),7.36 (2H, d), 7.44 (2H, m), 7.64-7.53 (2H, overlapping m), 7.64 (1H, d),7.88 (1H, s), 7.93 (1H, m), 7.99 (1H, s), 8.30 (1H, d), 8.36 (1H, m),8.58 (1H, s), 8.79 (1H, s), 9.03 (1H, s), 10.10 (1H, s). Route code*: 5Example 30:

R^(t) 1.77 min (Method 1); m/z 656 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 3.54 (2H, s), 5.33 (2H, s),6.35 (1H, s), 7.03 (1H, d), 7.06-7.09 (2H, overlapping m), 7.36 (2H, m),7.44 (2H, m), 7.54-7.67 (4H, overlapping m), 7.85 (1H, s), 7.93 (1H, m),8.04 (1H, s), 8.29 (1H, d), 8.39 (1H, m), 8.58 (1H, s), 8.79 (1H, s),9.09 (1H, s), 10.12 (1H, s). Route code*: 5 Example 31:

R^(t) 2.42 min (Method 1); m/z 605 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.26 (9H, s), 5.36 (2H, s), 6.31 (1H, s), 7.03- 7.10 (3H,overlapping m), 7.40 (1H, s), 7.62-7.67 (3H, overlapping m), 7.98-8.02(2H, overlapping m), 8.09 (1H, d), 8.22 (1H, m), 8.30 (1H, d), 8.40 (1H,m), 8.61 (1H, s), 8.67 (1H, s), 9.08 (1H, s), 10.20 (1H, s). Missing CH₃resonance presumed 2.50 ppm obscured by residual DMSO peak 2.49-2.52ppm. Route code*: 1 Example 32:

R^(t) 1.78 min (Method 1); m/z 656 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 3.54 (2H, s), 5.33 (2H, s),6.35 (1H, s), 7.03 (1H, d), 7.06-7.09 (2H, overlapping m), 7.36 (2H, m),7.44 (2H, m), 7.53-7.67 (4H, over- lapping m), 7.85 (1H, s), 7.92 (1H,m), 8.04 (1H, s), 8.29 (1H, dd), 8.39 (1H, m), 8.58 (1H, s), 8.79 (1H,s), 9.09 (1H, s), 10.12 (1H, s). Route code*: 5 Example 33:

R^(t) 1.83 min (Method 1); m/z 670 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 2.60 (3H, d), 3.55 (2H, s),5.33 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.07 (1H, dd), 7.36 (2H, m),7.44 (2H, m), 7.56-7.62 (2H, overlapping m), 7.64 (1H, d), 7.84 (1H, s),7.93 (1H, m), 8.01 (1H, m), 8.03 (1H, s), 8.29 (1H, d), 8.38 (1H, m),8.58 (1H, s), 8.79 (1H, s), 9.09 (1H, s), 10.12 (1H, s). Route: 5Example 34:

R^(t) 2.07 min (Method 1); m/z 641 (M + H)⁺ (ES⁺); 639 (M − H)⁻ (ES⁻);1H NMR (400 MHz, DMSO-d₆) δ: 0.85-0.95 (4H, overlapping m), 1.26 (9H,s), 2.02 (1H, m), 5.34 (2H, s), 6.31 (1H, s), 6.92 (2H, m), 6.99 (1H,d), 7.07 (1H, d), 7.32 (2H, m), 7.56-7.63 (3H, overlapping m), 7.89-7.94(2H, over- lapping m), 8.03 (1H, s), 8.28 (1H, d), 8.36 (1H, m), 8.48(1H, br s), 8.77 (1H, br s), 8.78 (1H, br s), 9.77 (1H, br s), 9.94 (1H,br s). Route code*: 1 with the hydroxy of compound (II) protectedthrough the process and deprotected as a final step Example 35:

R^(t) 2.08 min (Method 1); m/z 712.4 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.18 (9H, s), 2.31 (3H, s), 3.55-3.59 (8H, overlapping m),5.30 (2H, m), 6.26 (1H, s), 6.98 (1H, d), 7.07 (1H, d), 7.27 (2H, m),7.40 (2H, m), 7.50-7.53 (3 H, overlapping m), 7.90- 7.93 (2H,overlapping m), 8.27 (1H, d), 8.40 (1H, s), 8.50 (1H, m), 8.93 (1H, s),9.01 (1H, s), 9.06 (1H, s), 10.46 (1H, s). Route code*: 2 Example 36:

R^(t) 2.29 min (Method 1); m/z 696.4 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.27 (9H, s), 1.86 (4H, m), 2.34 (3H, s), 3.52 (2H, m),3.76 (2H, m), 5.37 (2H, m), 6.34 (1H, s), 7.02 (1H, d), 7.14 (1H, d),7.36 (2H, m), 7.44 (2H, m), 7.58- 7.64 (3H, overlapping m), 7.96 (1H,m), 8.02 (1H, s), 8.34 (1H, d), 8.40 (1H, m), 8.62 (1H, s), 8.85 (1H,s), 9.02 (1H, s), 9.09 (1H, s), 10.53 (1H, s). Route code*: 2 Example37:

R^(t) 2.11 min (Method 1); m/z 627 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ 1.22 (3H, t), 1.27 (9H, s), 2.39 (3H, s), 2.70 (2H, q), 5.34(2H, s), 6.35 (1H, s), 7.00- 7.07 (2H, overlapping m), 7.36 (2H, m),7.44 (2H, m), 7.58-7.67 (3H, overlapping m), 7.91 (1H, s), 7.94 (1H, m),8.11 (1H, d), 8.27 (1H, dd), 8.39 (1H, m), 8.59 (1H, s), 8.80 (1H, s),9.02 (1H, d), 9.98 (1H, s). Route code*: 1 Example 38:

R^(t) 2.40 min (Method 2); m/z 615 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 3.83 (3H, s), 5.35 (2H, s), 6.34 (1H, s), 7.04(1H, d), 7.07-7.13 (3H, overlapping m), 7.46 (2H, m), 7.58-7.65 (3H,overlapping m), 7.92 (1H, m), 8.01 (1H, s), 8.09 (1H, d), 8.22 (1H, m),8.30 (1H, d), 8.40 (1H, m), 8.53 (1H, s), 8.78 (1H, s), 9.08 (1H, s),10.14 (1H, s). Route code*: 1 Example 39:

R^(t) 2.53 min (Method 2); m/z 629 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.24 (3H, s), 3.87 (3H, s), 5.36 (2H, s), 6.34(1H, s), 7.04 (1H, d), 7.08- 7.11 (2H, overlapping m), 7.32-7.34 (2H,overlapping m), 7.60-7.66 (3H, over- lapping m), 7.93 (1H, m), 8.02 (1H,s), 8.09 (1H, d), 8.22 (1H, m), 8.30 (1H, d), 8.39 (1H, m), 8.52 (1H,s), 8.80 (1H, s), 9.09 (1H, s), 10.15 (1H, s). Route code*: 1 Example40:

R^(t) 2.00 min (Method 1); m/z 599 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 2.41 (3H, s), 5.36 (2H, s), 6.37 (1H, s), 7.05(1H, d), 7.09 (1H, d), 7.26 (1H, d), 7.35-7.39 (2H, overlapping m), 7.44(1H, t), 7.60-7.64 (3H, overlapping m), 7.95 (1H, m), 8.02 (1H, s), 8.09(1H, d), 8.23 (1H, m), 8.31 (1H, d), 8.40 (1H, m), 8.61 (1H, s), 8.80(1H, s), 9.08 (1H, s), 10.16 (1H, s). Route code*: 1 Example 41:

R^(t) 1.79 min (Method 1); m/z 627 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.26-1.28 (15H, overlapping m), 2.99 (1H, m), 5.37 (2H, s),6.38 (1H, s), 7.06 (1H, d), 7.10 (1H, d), 7.44 (2H, m), 7.47 (2H, m),7.62-7.67 (3H, overlapping m), 7.96 (1H, m), 8.02 (1H, s), 8.10 (1H, d),8.22 (1H, m), 8.31 (1H, d), 8.40 (1H, m), 8.65 (1H, s), 8.83 (1H, s),9.08 (1H, s), 10.16 (1H, s). Route code*: 1 Example 42:

R^(t) 2.60 min (Method 2); m/z 613 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.26-1.28 (12H, overlapping m), 2.70 (2H, q), 5.36 (2H, s),6.37 (1H, s), 7.05 (1H, d), 7.09 (1H, d), 7.41 (2H, m), 7.46 (2H, m),7.61-7.66 (3H, overlapping m), 7.96 (1H, m), 8.02 (1H, s), 8.09 (1H, s),8.22 (1H, m), 8.32 (1H, d), 8.40 (1H, m), 8.62 (1H, s), 8.81 (1H, s),9.09 (1H, s), 10.16 (1H, s). Route code*: 1 Example 43:

R^(t) 2.22 min (Method 1); m/z 706 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.25 (9H, s), 2.49 (3H, s), 3.28 (3H, s), 3.48-3.45 (4H, m),5.40 (2H, s), 6.35 (1H, s), 6.83 (1H, s), 7.03-7.08 (2H, overlapping m),7.14 (1H, d), 7.57-7.62 (3H, overlapping m), 8.01 (1H, d), 8.11 (1H, s),8.36 (1H, d), 8.42-8.47 (2H, overlapping m), 8.67 (1H, s), 8.76 (1H, s),8.95 (1H, s), 9.06 (1H, s), 10.60 (1H, s). Route code*: 2 Example 44:

R^(t) 2.20 min (Method 1): m/z 706 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 3.28 (3H, s), 3.45- 3.48 (4H, overlapping m),5.40 (2H, s), 6.32 (1H, s), 7.08-7.04 (2H, overlapping m), 7.16 (1H, d),7.40 (1H, s), 7.57-7.62 (3H, overlapping m), 8.01 (1H, d), 8.11 (1H, s),8.36 (1H, d), 8.42-8.46 (2H, over- lapping m), 8.62 (1H, s), 8.76 (1H,s), 8.88 (1H, s), 9.06 (1H, s), 10.60 (1H, s). 3H from CH₃—Ar assumed tobe under DMSO. Route code*: 2 Example 45:

R^(t) 2.00 min (Method 1); m/z 619 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 5.36 (2H, s), 6.38 (1H, s), 7.05 (1H, d), 7.10(1H, d), 7.60-7.64 (7H, overlapping m), 7.92 (1H, m), 8.02 (1H, s), 8.09(1H, d), 8.22 (1H, m), 8.31 (1H, d), 8.40 (1H, m), 8.65 (1H, s), 8.77(1H, s), 9.08 (1H, s), 10.16 (1H, s). Route code*: 1 Example 46:

R^(t) 1.99 min (Method 1); m/z 649 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 3.94 (3H, s), 5.36 (2H, s), 6.35 (1H, s),7.04- 7.13 (2H, overlapping m), 7.32 (1H, s), 7.34 (1H, s), 7.53 (1H,m), 7.58-7.68 (3H, overlapping m), 7.93 (1H, m), 8.01 (1H, s), 8.10 (1H,d), 8.22 (1H, m), 8.30 (1H, d), 8.42 (1H, m), 8.58 (1H, s), 8.77 (1H,s), 9.09 (1H, s), 10.16 (1H, s). Route code*: 1 Example 47:

R^(t) 2.86 min (Method 2); m/z 653 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.77 (1H, m), 1.93 (1H, m), 2.14-2.35 (4H,over- lapping m), 2.40 (3H, s), 3.57 (1H, pentet), 5.35 (2H, s), 6.36(1H, s), 7.02 (1H, d), 7.08 (1H, m), 7.37 (2H, m), 7.45 (2H, m),7.55-7.67 (3H, overlapping m), 7.93 (1H, m), 7.97 (1H, s), 8.07 (1H, s),8.31 (1H, dd), 8.37 (1H, m), 8.59 (1H, s), 8.80 (1H, s), 8.92 (1H, s),10.09 (1H, s). Route code*: 1 Example 48:

R^(t) 2.94 min (Method 2); m/z 667 (M + H)⁺ (space) (ES⁺); ¹H NMR (400MHz, DMSO- d₆) δ: 1.28 (9H, s), 1.46-1.58 (2H, overlapping m), 1.59-1.77 (4H, overlapping m), 1.87-2.02 (2H, overlapping m), 2.40 (3H, s),3.08 (1H, pentet), 5.33 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.08 (1H,d), 7.37 (2H, m), 7.45 (2H, m), 7.5-7.69 (3H, overlapping m), 7.94 (1H,d), 7.99 (1H, s), 8.09 (1H, s), 8.30 (1H, d), 8.34 (1H, m), 8.59 (1H,s), 8.80 (1H, s), 8.84 (1H, s), 10.04 (1H, s). Route code*: 1 Example49:

R^(t) 2.55 min (Method 2); m/z 603 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 5.36 (2H, s), 6.39 (1H, s), 7.04 (1H, d), 7.09(1H, d), 7.28 (1H, t), 7.45- 7.51 (2H, overlapping m), 7.58-7.68 (4H,overlapping m), 7.93 (1H, m), 8.01 (1H, s), 8.10 (1H, d), 8.21 (1H, m),8.31 (1H, d), 8.40 (1H, m), 8.68 (1H, s), 8.81 (1H, s), 9.09 (1H, s),10.16 (1H, s). Route code*: 1 Example 50:

R^(t) 2.6 min (Method 2): m/z 619 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 5.36 (2H, s), 6.39 (1H, s), 7.04 (1H, d), 7.09(1H, d), 7.48 (1H, m), 7.55- 7.68 (6H, overlapping m), 7.93 (1H, m),8.01 (1H, s), 8.10 (1H, d), 8.21 (1H, m), 8.30 (1H, d), 8.40 (1H, m),8.67 (1H, s), 8.79 (1H, s), 9.08 (1H, s), 10.16 (1H, s). Route code*: 1Example 51:

R^(t) 2.6 min (Method 2); m/z 613 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 2.30 (3H, s), 2.31 (3H, s), 5.34 (2H, s), 6.35(1H, s), 7.04 (1H, d), 7.09 (1H, d), 7.27 (1H, m), 7.30- 7.33 (2H,overlapping m), 7.59-7.66 (3H, overlapping m), 7.93 (1H, m), 8.01 (1H,s), 8.10 (1H, d), 8.21 (1H, m), 8.31 (1 H, d), 8.40 (1H, m), 8.56 (1H,s), 8.80 (1H, s), 9.08 (1H, s), 10.16 (1H, s). Route code*: 1 Example52:

R^(t) 2.7 min (Method 2); m/z 667 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 5.36 (2H, s), 6.38 (1H, s), 7.04 (1H, d), 7.10(1H, d), 7.55 (1H, d), 7.59- 7.65 (3H, overlapping m), 7.79 (1H, d),7.85-7.90 (2H, overlapping m), 8.01 (1H, s), 8.09 (1H, d), 8.21 (1H, m),8.30 (1H, d), 8.39 (1H, m), 8.65 (1H, s), 8.76 (1H, s), 9.08 (1H, s),10.16 (1H, s). 3H from CH₃—Ar assumed to be under DMSO. Route code*: 1*Route codes: 1: compound (I) (which might optionally be protected)prepared by reaction of compound (II) with compound (III); compound(III) prepared by deprotection of compound (IX); compound (IX) preparedby reaction of compound (XVI) with compound (XIII). This route isillustrated in the synthesis of Example 2. 2: compound (I) (which mightoptionally be protected) prepared by reaction of compound (II) withcompound (III); compound (III) prepared by reduction of compound (VIII);compound (VIII) prepared by reaction of compound (XI) with compound (V)This route is illustrated in the synthesis of Example 5. 3: compound (I)prepared by reaction of compound (II) with compound (III); compound(III) prepared by reduction of compound (VIII); compound (VIII) preparedby reaction of compound (XII) with compound (XIII). This route isillustrated in the synthesis of Example 1. 4: compound (I) prepared froma compound of formula (VI); compound of formula (VI) prepared byreaction of compound (II) with compound (III′). Compound (III′) preparedby a process analogous to that for the preparation of compound (III) inroute code 3 with the COOH group protected as the methyl ester for thenitro reduction step. This route is illustrated in the synthesis ofExample 7. 5: compound (I) prepared by reaction of compound (II) withcompound (III); compound (III) prepared by reduction of compound (VIII);compound (VIII) prepared from a compound of formula (XIVa/b); compoundof formula (XIVa/b) prepared by hydrolysis of the corresponding methylester; methyl ester prepared by a process analogous to that for thepreparation of compound (VIII) in route code 2. This route isillustrated in the synthesis of Example 8.

Example 53:5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamideIntermediate EE: Ethyl5-((4-(((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)methyl)pyridin-2-ylamino)pyrazine-2-carboxylate

To a suspension of tert-butyl(4-((2-chloropyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (12.5 g,32.5 mmol), ethyl 5-aminopyrazine-2-carboxylate (6.52 g, 39.0 mmol),Pd₂(dba)₃ (1.487 g, 1.624 mmol) and BINAP (2.022 g, 3.25 mmol) in1,4-dioxane (55 mL, 32.5 mmol) at room temperature and under nitrogenwas added cesium carbonate (15.87 g, 48.7 mmol). The suspension wassonicated for 5 min and degassed for 10 min before being stirred at 90°C. overnight. The reaction mixture was cooled to room temperature, anddiluted with a solution of 10% MeOH in DCM (750 mL), methanol (100 mL)and 1,4-dioxane (100 mL) before being filtered through a pad of Celite.The filtrate was concentrated in vacuo to give a residue which wassuspended in EtOH (500 mL) before being stirred for 16 h and the solidcollected via filtration. The solid was dried in a vacuum oven at 40° C.for 3 h, then slurried in diethyl ether (30 mL) for 10 min and filteredto afford the subtitle compound5-((4-(((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylateas a light yellow solid (7 g, 37%); R^(t) 2.62 min (Method 1); m/z 516(M+H)⁺ (ES⁺).

Intermediate FF:5-((4-(((4-((tert-Butoxycarbonyl)amino)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylic acid

A solution of lithium hydroxide (1.463 g, 61.1 mmol) in water (100 mL)was added to a suspension of ethyl5-((4-(((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylate (Intermediate EE) (7 g, 13.58mmol) in tetrahydrofuran (100 mL). The reaction mixture was heated at40° C. for 4 h then stirred at room temperature overnight. The organiclayer was evaporated, and the residual solid material isolated byfiltration, washing with additional water. This solid was then taken upin water and the mixture acidified with 1M HCl. The resulting solid wasisolated by filtration, washing with water (200 mL) and hexane (200 mL),and dried under vacuum at 40° C. to afford the subtitle compound5-((4-(((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid as a light yellow solid (5 g, 68%); R^(t) 1.91 min (Method 1); m/z488 (M+H)⁺ (ES⁺).

Intermediate GG: tert-Butyl(4-((2-((5-((2-hydroxyethyl)carbamoyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate

2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (V) (5.62 g, 14.77 mmol) was added to a suspensionof5-((4-(((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxylicacid (Intermediate FF) (4.8 g, 9.85 mmol) in dry DMF (144 mL, 1861mmol). After 20 min of stirring at room temperatureN-ethyl-N-isopropylpropan-2-amine (5.14 mL, 29.5 mmol) was addedfollowed by 2-aminoethanol (1.783 mL, 29.5 mmol). The reaction mixturewas heated to 40° C. overnight, then cooled to 0° C. and saturatedaqueous NaHCO₃ (350 mL) was added. The resultant slurry was stirred for20 min, whereafter the solid was collected by filtration under reducedpressure and washed with water (100 mL). The solid was dried undervacuum overnight to afford the subtitle compound tert-butyl(4-((2-((5-((2-hydroxyethyl)carbamoyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamateas a yellow solid (9 g, 153% yield), which was used in the next reactionwithout further purification; R^(t) 1.73 min (Method 1); m/z 531 (M+H)⁺(ES⁺).

Intermediate HH:5-((4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamide

A suspension of tert-butyl(4-((2-((5-((2-hydroxyethyl)carbamoyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate(Intermediate GG) (523 g, 9.85 mmol) in DCM (44 mL) was treated withhydrogen chloride in 1,4-dioxane (49.3 mL, 197 mmol). The reactionmixture was allowed to stir at room temperature for 1 h. Saturatedaqueous NaHCO₃ (250 mL) was added slowly and the quenched mixture wasallowed to stir at room temperature overnight. The resultant solid wasfiltered and washed with water (2×200 mL), and dried under vacuum at 40°C. overnight to afford the subtitle compound5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamideas a yellow solid (2.1 g, 48% yield); R^(t) 1.00 min (Method 1); m/z 431(M+H)⁺ (ES⁺).

5-((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamide

To a stirred slurry of5-((4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamide(Intermediate HH) (2 g, 4.65 mmol) in THF (57.1 mL) at room temperatureunder a nitrogen atmosphere was added phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (1.786 g, 5.11mmol). The reaction mixture was stirred for 5 min, then Et₃N (0.648 mL,4.65 mmol) was added over 2 min and the reaction mixture stirred at 40°C. for 20 min. THF (50 mL) was then added and stirring continuedovernight. Solvent was removed in vacuo and the solid was suspended in10% MeOH, and adsorbed onto silica. The crude product was purified bychromatography on silica gel (80 g column, gradient 0-30% MeOH in DCM)to afford the title compound5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamideas a dark orange solid (2.5 g, 74%); R^(t) 1.94 min (Method 1); m/z 686(M+H)⁺ (ES⁺); ¹H NMR δ: 1.28 (9H, s), 2.40 (3H, s), 3.39 (2H, m), 3.54(2H, m), 4.80 (1H, t), 5.39 (2H, s), 6.37 (1H, s), 7.05 (1H, d), 7.16(1H, d), 7.36 (2H, m), 7.45 (2H, m), 7.56-7.68 (3H, overlapping m), 7.96(1H, m), 8.10 (1H, s), 8.35 (1H, d), 8.39-8.47 (2H, overlapping m), 8.63(1H, s), 8.77 (1H, d), 8.84 (1H, s), 9.06 (1H, d), 10.59 (1H, s).

Example 54:(S)-5-(4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-methoxypiperidin-1-yl)ethyl)pyrazine-2-carboxamideIntermediate II:N-(2-Bromoethyl)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide

To a well stirred slurry of5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-hydroxyethyl)pyrazine-2-carboxamide(Example 53) (0.254 g, 0.370 mmol) in anhydrous MeCN (12.7 mL) at roomtemperature under a nitrogen atmosphere were added triphenylphosphine(0.291 g, 1.111 mmol) and carbon tetrabromide (0.368 g, 1.111 mmol). Thereaction mixture was stirred overnight. The resultant precipitate wasisolated by filtration, washing with MeCN (50 mL), then dissolved in DMFand adsorbed onto silica gel. The crude product was purified bychromatography on silica gel (12 g column, gradient 0-15% MeOH in DCM)to afford the subtitle compoundN-(2-bromoethyl)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide)as a pale yellow solid (0.1 g, 35%); R^(t) 2.37 min (Method 1); m/z748/750 (M+H)⁺ (ES⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (9H, s), 2.39(3H, s), 3.54-3.72 (4H, overlapping m), 5.40 (2H, s), 6.35 (1H, s), 7.04(1H, d), 7.19 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.69 (3H,overlapping m), 7.95 (1H, m), 8.08 (1H, s), 8.36 (1H, d), 8.41 (1H, m),8.60 (1H, s), 8.77 (1H, d), 8.79-8.85 (2H, overlapping m), 9.02 (1H, d),10.72 (1H, s).

(S)-5-((4-(((4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-methoxypiperidin-1-yl)ethyl)pyrazine-2-carboxamide

To a stirred solution of (S)-3-methoxypiperidine hydrochloride (0.608 g,4.01 mmol) in anhydrous MeCN (15.0 mL) at room temperature under anitrogen atmosphere was added Hunig's base (0.525 mL, 3.01 mmol) and thesolution was stirred for 1 h beforeN-(2-bromoethyl)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine-2-carboxamide(0.150 g, 0.200 mmol) was added in a single portion. The stirring wascontinued for 2 days and then the resultant precipitate was isolated byfiltration, washing with MeCN (10 mL). The crude product was purified bypreparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, WatersX-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water) toafford the title compound(S)-5-((4-(((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-(3-methoxypiperidin-1-yl)ethyl)pyrazine-2-carboxamideas a pale orange solid (28 mg, 18%); R^(t) 1.72 min (Method 1); m/z 783(M+H)⁺ (ES⁺); ¹H NMR δ: 1.00-1.24 (3H, overlapping m), 1.28 (9H, s),1.42 (1H, m), 1.66 (1H, m), 1.81-2.04 (3H, overlapping m), 2.40 (3H, s),2.69 (1H, m), 2.98 (1H, d), 3.20 (1H, dq), 3.26 (3H, s), 3.42 (2H, q),5.39 (2H, s), 6.36 (1H, s), 7.05 (1H, d), 7.17 (1H, dd), 7.36 (2H, m),7.45 (2H, m), 7.57-7.69 (3H, overlapping m), 7.95 (1H, m), 8.10 (1H, s),8.35 (1H, m), 8.39-8.47 (2H, overlapping m), 8.64 (1H, s), 8.76 (1H, d),8.84 (1H, s), 9.06 (1H, d), 10.59 (1H, s).

Example 55:1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(pyrrolidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaIntermediate JJ: 4-(((4-Aminonaphthalen-1-yl)oxy)methyl)pyridin-2-amine

A solution of 4-(((4-nitronaphthalen-1-yl)oxy)methyl)pyridin-2-amine (3g, 3.39 mmol) in THF (20 mL) and AcOH (few drops) was hydrogenated inthe H-Cube (10% Pd/C, 55×4 mm, Full hydrogen, 45° C., 1 mL/min). Thereaction mixture was concentrated in vacuo to afford the subtitlecompound 4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-amine as ablack solid (2.3 g, 71% yield); R^(t) 0.35 min (Method 1); m/z 266(M+H)⁺ (ES⁺).

Intermediate KK:1-(4-((2-Aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To a stirred solution of4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-amine (Intermediate JJ)(2.3 g, 8.67 mmol) in THF (40 mL) was added phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (3.33 g, 9.54mmol) and triethylamine (0.224 mL, 1.734 mmol). The reaction mixture wasstirred at 40° C. for 1 h before being allowed to cool and stirred atroom temperature overnight. The reaction mixture was absorbed ontosilica and purified by chromatography on silica gel (80 g column,gradient 0-10% MeOH in DCM) to afford the subtitle compound1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureaas a black solid (441 mg, 9% yield); R^(t) 1.81 min (Method 1); m/z 521(M+H)⁺ (ES⁺).

1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(pyrrolidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea

A mixture of1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(150 mg, 0.288 mmol), 2-chloro-6-(pyrrolidin-1-yl)pyrazine (52.9 mg,0.288 mmol), Pd₂(dba)₃ (13.19 mg, 0.014 mmol), BINAP (17.94 mg, 0.029mmol) and sodium tert-butoxide (41.5 mg, 0.432 mmol) was flushed withnitrogen and suspended in 1,4-dioxane (2.1 mL). The resulting mixturewas sonicated for 2 min, degassed with nitrogen for 5 min and heated at90° C. for 3 h. The reaction mixture was allowed to cool to roomtemperature, diluted with 2 mL 10% MeOH in DCM, sonicated for 1 min, andfiltered through Celite, washing with 10% MeOH in DCM (2×4 mL). Thefiltrate was concentrated in vacuo, and the crude product purified firstby preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, WatersX-Select Prep-C18, 5 μm, 19×50 mm column, 30-60% MeCN in Water), then byfiltering through a column of with 0.7M ammonia in MeOH (25 mL), to givethe title compound1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(pyrrolidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)ureaas a beige solid (36 mg, 18% yield); R^(t) 2.12 min (Method 1); m/z 668(M+H)⁺ (ES⁺); ¹H NMR δ:1.26 (9H, s), 1.70 (4H, m), 2.38 (3H, s), 5.32(2H, s), 6.34 (1H, s), 6.97 (1H, d), 7.02 (1H, d), 7.32-7.36 (3H,overlapping m), 7.43 (2H, m), 7.53-7.63 (3H, overlapping m), 7.92 (1H,m), 7.98 (1H, s), 8.22-8.26 (2H, overlapping m), 8.29 (1H, m), 8.60 (1H,br s), 8.80 (1H, br s), 9.64 (1H, s), Missing (CH₂)₂ resonance presumed3.31 ppm (4H, s) obscured by H₂O peak 3.29-3.34 ppm.

Examples 56-288

The following examples were prepared using methods analogous to thosedescribed above for the preparation of Examples 1-10 and 53-55:

Example 56:

R^(t) 2.15 min (Method 1); m/z 740 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.46 (2H, m), 1.88 (2H, m), 2.39 (3H, s), 3.27(3H, s), 3.29-3.50 (3H, over- lapping m), 3.77 (1H, m), 3.93 (1H, m),5.38 (2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.15 (1H, d), 7.36 (2H, m),7.44 (2H, m), 7.57-7.66 (3H, overlapping m), 7.92-8.00 (2H, overlappingm), 8.34 (1H, d), 8.39 (1H, m), 8.46 (1H, s), 8.61 (1H, s), 8.82 (1H,s), 9.05 (1H, s), 10.54 (1H, s). Route code*: 2 Example 57:

Rt 2.57 min (Method 2); m/z 629 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 2.22 (3H, s), 3.84 (3H, s), 5.35 (2H, s), 6.37(1H, s), 7.00-7.13 (4H, over- lapping m), 7.30 (1H, d), 7.57-7.68 (3H,overlapping m), 7.94 (1H, m), 8.01 (1H, s), 8.09 (1H, d), 8.21 (1H, dd),8.30 (1H, d), 8.40 (1H, m), 8.60 (1H, s), 8.83 (1H, s), 9.08 (1H, d),10.15 (1H, s). Route code*: 1 Example 58:

R^(t) 2.69 min (Method 2); m/z 627 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.36 (3H, s), 2.38 (3H, s), 2.40 (3H, s), 5.33(2H, s), 6.36 (1H, s), 6.99- 7.04 (2H, overlapping m), 7.25 (1H, d),7.33-7.46 (3H, overlapping m), 7.56-7.65 (3H, overlapping m), 7.87 (1H,s), 7.93 (1H, m), 8.25 (1H, d), 8.40 (1H, m), 8.60 (1H, s), 8.79 (1H,s), 8.88 (1H, s), 9.88 (1H, s). Route code*: 1 Example 59:

R^(t) 2.02 min (Method 1); m/z 309 (M + 2H)²⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.27 (9H, s), 2.31 (3H, s), 5.36 (2H, s), 6.36 (1H, s),7.04 (1H, d), 7.08 (1H, d), 7.30-7.51 (3H, over- lapping m), 7.56-7.65(3H, overlapping m), 7.94 (1H, m), 8.01 (1H, s), 8.09 (1H, m), 8.21 (1H,d), 8.30 (1H, d), 8.40 (1H, m), 8.63 (1H, s), 8.79 (1H, s), 9.08 (1H,s), 10.15 (1H, s). Route code*: 1 Example 60:

R^(t) 1.88 min (Method 1); m/z 714 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.40 (3H, s), 3.03 (2H, s), 3.13 (1H, s), 3.16(2H, s), 3.30 (1H, s), 3.55 (2H, m), 3.67 (2H, m), 5.39 (2H, s), 6.36(1H, s), 7.04 (1H, d), 7.14 (1H, d), 7.35 (2H, m), 7.44 (2H, m), 7.59-7.66 (3H, overlapping, m), 7.95 (1H, m), 8.10 (1H, s), 8.34 (1H, d),8.40 (1H, m), 8.45 (1H, m), 8.59 (1 H, s), 8.80 (1H, d), 9.09 (1H, d),10.47 (1H, s). Route code*: 2 Example 61:

Rt 2.36 min (Method 2); m/z 629 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.41 (3H, s), 4.54 (2H, s), 5.35 (2H, s), 6.36(1H, s), 7.01-7.08 (2H, over- lapping m), 7.25 (1H, d), 7.32-7.47 (3H,overlapping m), 7.58-7.65 (3H, over- lapping m), 7.93 (1H, m), 7.97 (1H,s), 8.26 (1H, s), 8.29 (1H, d), 8.40 (1H, m), 8.61 (1H, s), 8.80 (1H,s), 9.02 (1H, s), 10.11 (1H, s). Route code*: 1 Example 62:

R^(t) 2.10 min (Method 1); m/z 316 (M + 2H)²⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.18 (3H, t), 1.28 (9H, s), 2.62 (2H, q), 5.35 (2H, s),6.38 (1H, s), 7.01 (1H, d), 7.06 (1H, dd), 7.26 (1H, m), 7.47 (2H, m),7.54-7.66 (4H, overlapping m), 7.93 (1H, m), 7.98 (1H, s), 8.02 (1H, s),8.29 (1H, d), 8.38 (1H, m), 8.68 (1H, s), 8.80 (1H, s), 8.91 (1H, s),10.07 (1H, s). Route code*: 1 Example 63:

R^(t) 2.54 min (Method 2); m/z 644 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.17 (3H, t), 1.27 (9H, s), 2.62 (2H, q), 3.94 (3H, s), 5.35(2H, s), 6.37 (1H, s), 6.99- 7.03 (2H, overlapping m), 7.06 (1H, d),7.54-7.64 (3H, overlapping m), 7.85-7.91 (2H, overlapping m), 7.98 (1H,s), 8.01 (1H, s), 8.29 (1H, d), 8.34-8.40 (2H, overlapping m), 8.63 (1H,s), 8.75 (1H, s), 8.91 (1H, s), 10.06 (1H, s). Route code*: 1 Example64:

Rt 2.37 min (Method 1); m/z 315 (M + 2H)²⁺ (ES+); 1H NMR (400 MHz, DMSO-d₆) δ: 1.28 (9H, s), 3.33 (3H, s), 4.50 (2H, s), 5.35 (2H, s), 6.37 (1H,s), 7.03 (1H, d), 7.08 (1H, d), 7.36 (1H, m), 7.49-7.54 (3H, over-lapping m), 7.57-7.65 (3H, overlapping m), 7.94 (1H, m), 8.01 (1H, s),8.09 (1H, d), 8.22 (1H, d), 8.30 (1H, d), 8.39 (1H, m), 8.71 (2H, s),9.08 (1H, d), 10.15 (1H, s). Route code*: 1 Example 65:

R^(t) 2.14 min (Method 1); m/z 696 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.86-1.89 (4H, m), 2.36 (3H, s), 3.51 (2H, t),3.74 (2H, t), 5.36 (2H, s), 6.36 (1H, s), 7.04 (1H, d), 7.14 (1H, d),7.25 (1H, d), 7.35-7.42 (2H, overlapping, m), 7.45 (1H, m), 7.60-7.64(3H, overlapping, m), 7.95 (1H, m), 8.02 (1H, s), 8.35 (1H, d), 8.40(1H, m), 8.59- 8.62 (2H, overlapping, m), 8.78 (1H, s), 9.08 (1H, d),10.50 (1H, s). Route code*: 2 Example 66:

R^(t) 2.20 min (Method 1); m/z 726 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.86-2.08 (2H, over- lapping m), 2.39 (3H, s),rotamers: 3.21 (1.5H, s), 3.26 (1.5H, s), 3.43-3.66 (2H, m), 3.72-3.90(2H, overlapping m), 3.99 (1H, m), 5.38 (2H, s), 6.36 (1H, s), 7.04 (1H,d), 7.14 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.57-7.68 (3H, overlappingm), 7.94 (1H, m), 8.02 (1H, s), 8.34 (1H, d), 8.41 (1H, m), 8.60 (1H,s), 8.62 (1H, m), 8.81 (1H, s), 9.09 (1H, d), 10.55 (1H, d). Routecode*: 6 Example 67:

R^(t) 2.19 min (Method 1); m/z 726 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.85-2.08 (2H, over- lapping m), 2.39 (3H, s),rotamers: 3.21 (1.5H, s), 3.27 (1.5H, s), 3.45-3.65 (2H, m), 3.72-3.90(2H, overlapping m), 3.99 (1H, m), 5.38 (2H, s), 6.36 (1H, s), 7.04 (1H,d), 7.14 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.68 (3H, overlappingm), 7.94 (1H, m), 8.02 (1H, s), 8.34 (1H, d), 8.41 (1H, m), 8.61 (1H,s), 8.63 (1H m), 8.81 (1H, s), 9.09 (1H, d), 10.55 (1H, d). Route code*:6 Example 68:

Rt 2.35 min (Method 1); m/z 841 (M + H)⁺ (ES+); 1H NMR (400 MHz,DMSO-d₆) δ: 1.17 (6H, d), 1.28 (9H, s), 2.40 (3H, s), 2.90 (1H, m), 5.36(2H, s), 6.36 (1H, s), 7.00 (1H, d), 7.07 (1H, d), 7.37 (2H, m), 7.43(2H, m), 7.56-7.64 (3H, overlapping m), 7.93 (1H, d), 7.99 (1H, s), 8.07(1H, s), 8.30 (1H, d), 8.37 (1H, d), 8.58 (1H, s), 8.79 (1H, s), 8.86(1H, s), 10.04 (1H, s). Route code*: 1 Example 69:

R^(t) 1.97 min (Method 1); m/z 712 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.74-1.96 (2H, over- lapping m), 2.40 (3H, s),3.40-3.66 (3H, overlapping m), 3.84 (1H m), 4.31 (1H, m), 4.96 (1H, m),5.38 (2H, s), 6.36 (1H, s), 7.04 (1H, d), 7.14 (1H, d), 7.24 (1H m),7.33-7.46 (3H, overlapping m), 7.57-7.65 (3H, over- lapping m), 7.94(1H, m), 8.02 (1H, s), 8.35 (1H, d), 8.40 (1H, m), 8.62 (1H, m), 8.69(1H, s), 8.87 (1H, s), 9.09 (1H, s), 10.51 (1H, s). Route code*: 6Example 70:

R^(t) 2.25 min (Method 1); m/z 329 (M + 2H)²⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.17 (3H, t), 1.28 (9H, s), 2.22 (3H, s), 2.62 (2H, q),3.84 (3H, s), 5.35 (2H, s), 6.37 (1H, s), 6.99-7.07 (3H, overlapping m),7.11 (1H, d), 7.30 (1H, m), 7.55-7.68 (3H, overlapping m), 7.93 (1H, m),7.98 (1H, s), 8.02 (1H, s), 8.29 (1H, d), 8.38 (1H, m), 8.59 (1H, s),8.82 (1H, s), 8.91 (1H, s), 10.06 (1H, s). Route code*: 1 Example 71:

R^(t) 2.15 min (Method 1); m/z 726 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.83-1.88 (4H, m), 3.35 (3H, s), 3.52 (2H, t),3.74 (2H, t), 4.50 (2H, s), 5.38 (2H, s), 6.38 (1H, s), 7.04 (1H, d),7.15 (1H, d), 7.50 (2H, m), 7.56 (2H, m), 7.60-7.65 (3H, overlapping,m), 7.90-7.94 (1H, m), 8.02 (1H, s), 8.35 (1H, d), 8.41 (1H, m), 8.59-8.62 (2H, overlapping, m), 8.81 (1 H, s), 9.09 (1H, d), 10.50 (1H, s).Route code*: 2 Example 72:

R^(t) 2.05 min (Method 1); m/z 728 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.20 (6H, s), 1.27 (9H, s), 1.65 (2H, t), 2.40 (3H, s), 3.41(2H, q), 4.45 (1H, s), 5.38 (2H, s), 6.36 (1H, s), 7.04 (1H, d), 7.15(1H, d), 7.38 (2H, m), 7.44 (2H, m), 7.58- 7.66 (3H, overlapping, m),7.95 (1H, m), 8.10 (1H, s), 8.34 (1H, d), 8.42 (1H, m), 8.59 (1H, s),8.64 (1H, t), 8.75 (1 H, d), 8.81 (1H, s), 9.06 (1H, d), 10.58 (1H, s).Route code*: 6 Example 73:

R^(t) 2.16 min (Method 1); m/z 758 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.39 (3H, s), 3.15 (3H, s), 3.29 (3H, s), 3.52(4H, m), 3.68 (4H, m), 5.37 (2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.14(1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.57- 7.67 (3H, overlapping m),7.94 (1H, m), 7.98 (1H, s), 8.34 (1H, d), 8.40 (1H, m), 8.45 (1H, s),8.58 (1H, s), 8.79 (1H, s), 9.06 (1H, s), 10.46 (1H, s). Route code*: 6Example 74:

R^(t) 2.10 min (Method 1); m/z 728 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.13 (6H, s), 1.27 (9H, s), 2.34 (3H, s), 3.17 (3H, s), 3.38(2H, d), 5.39 (2H, s), 6.36 (1H, s), 7.04 (1H, d), 7.17 (1H, d),7.35-7.40 (2H, over- lapping, m), 7.43-7.48 (2H, overlapping, m),7.60-7.67 (3H, overlapping, m), 7.92- 7.97 (1H, m), 8.03 (1H, t), 8.08(1H, s), 8.35 (1H, d), 8.39-8.44 (1H, m), 8.59 (1H, s), 8.77 (1H, d),8.81 (1H, s), 9.10 (1H, d), 10.63 (1H, s). Route code*: 6 Example 75:

R^(t) 1.9 min (Method 1); m/z 585 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.29 (9H, s), 5.36 (2H, s), 6.38 (1H, s), 7.04 (1H, d), 7.09(1H, d), 7.44 (1H, m), 7.64- 7.55 (7H, overlapping m), 7.94 (1H, m),8.02 (1H, s), 8.10 (1H, d), 8.22 (1H, m), 8.31 (1H, d), 8.40 (1H, m),8.65 (1H, s), 8.81 (1H, s), 9.09 (1H, d), 10.15 (1H, s). Route code*: 1Example 76:

R^(t) 2.22 min (Method 1); m/z 380 (M + 2H)²⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.28 (9H, s), 2.40 (3H, s), 3.15 (3H, s), 3.29 (3H, s),3.52 (4H, dt), 3.68 (4H, dt), 5.37 (2H, s), 6.36 (1H, s), 7.04 (1H, d),7.13 (1H, dd), 7.25 (1H, d), 7.33-7.47 (3H, overlapping m), 7.56- 7.68(3H, overlapping m), 7.93 (1H, m), 7.98 (1H, s), 8.34 (1H, d), 8.34 (1H,m), 8.46 (1H, d), 8.60 (1H, s), 8.79 (1H, s), 9.06 (1H, d), 10.46 (1H,s). Route code*: 6 Example 77:

R^(t) 2.08 min (Method 1); m/z 316 (M + 2H)²⁺ (ES⁺); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.28 (9H, s), 2.53 (3H, s), 5.36 (2H, s), 6.37 (1H, s),7.03 (1H, d), 7.08 (1H, dd), 7.26-7.37 (2H, m), 7.40- 7.52 (2H, m),7.56-7.65 (3H, m), 7.88-7.97 (1H, m), 8.01 (1H, s), 8.09 (1H, d), 8.19-8.24 (1H, m), 8.30 (1H, d), 8.36-8.43 (1H, m), 8.65 (1H, s), 8.81 (1H,s), 9.08 (1H, d), 10.17 (1H, s) Route code*: 1 Example 78:

R^(t) 1.53 min (Method 1); m/z 629 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 3.12 (6H, s), 5.36 (2H, s), 6.35 (1H, s), 6.80(1H, d) 7.04 (1H, d), 7.10 (1H, d), 7.68-7.57 (4H, over- lapping m),7.93 (1H, m), 8.01 (1H, s), 8.10 (1H, d), 8.24-8.20 (2H, overlapping m),8.31 (1H, d), 8.40 (1H, m), 8.57 (1H, s), 8.81 (1H, s), 9.08 (1H, d),10.19 (1H, s). Route code*: 1 Example 79:

R^(t) 1.75 min (Method 1); m/z 753 (M + H)⁺ (ES+); ¹H NMR (400 MHz,DMSO- d₆) δ: 1.26 (9H, s), 1.32- 1.62 (6H, overlapping m), 2.36-2.51(9H, overlapping m), 3.35-3.55 (2H, over- lapping m), 5.38 (2H, s), 6.34(1H, s), 7.03 (1H, d), 7.16 (1H, d), 7.35 (2H, m), 7.43 (2H, m),7.57-7.66 (3H, overlapping m), 7.93 (1H, m), 8.08 (1H, s), 8.32-8.42(3H, overlapping m), 8.61 (1H, s), 8.75 (1H, s), 8.82 (1H, s), 9.05 (1H,s), 10.61 (1H, s). Route code*: 6 Example 80:

R^(t) 1.66 min (Method 1); m/z 739 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.64-1.79 (4H, over- lapping m), 2.11 (2H, m),2.24 (3H, br s), 2.39 (3H, s), 2.82 (2H, m), 3.80 (1H, br s), 5.38 (2H,s), 6.36 (1H, s), 7.03 (1H, d), 7.15 (1H, d), 7.36 (2H, m), 7.45 (2H,m), 7.58-7.67 (3H, overlapping m), 7.94 (1H, m), 8.10 (1H, s), 8.33-8.43(3H, overlapping m), 8.61 (1H, s), 8.73 (1H, s), 8.81 (1H, s), 9.05 (1H,s), 10.58 (1H, s). Route code*: 6 Example 81:

R^(t) 1.70 min (Method 1); m/z 753 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.18-1.30 (11H, overlapping m), 1.52-1.70 (3H, over- lappingm), 2.03 (2H, m), 2.26 (3H, br s), 2.82 (3H, s), 2.87 (2H, m), 3.19 (2H,t), 5.38 (2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.16 (1H, d), 7.36 (2H,m), 7.44 (2H, m), 7.58-7.67 (3H, overlapping m), 7.94 (1H, m), 8.09 (1H,s), 8.35 (1H, d), 8.41 (1H, m), 8.58-8.65 (2H, over- lapping m), 8.74(1H, s), 8.83 (1H, s), 9.05 (1H, s), 10.59 (1H, s). Route code*: 6Example 82:

R^(t) 1.63 min (Method 1); m/z 725 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.77 (1H, m), 2.17 (1H, m), 2.26 (3H, s),2.32- 2.54 (3H, overlapping m), 2.61-2.69 (2H, overlapping m), 2.66 (2H,m), 4.41 (1H, m), 5.38 (2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.16 (1H,d), 7.36 (2H, m), 7.44 (2H, m), 7.57-7.67 (3H, overlapping m), 7.94 (1H,m), 8.10 (1H, s), 8.30-8.36 (2H, over- lapping m), 8.41 (1H, m), 8.59(1H, s), 8.73 (1H, s), 8.80 (1H, s), 9.04 (1H, s), 10.58 (1H, s). Routecode*: 6 Example 83:

R^(t) 1.64 min (Method 1); m/z 725 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.77 (1H, m), 2.17 (1H, m), 2.32-2.56 (8H,over- lapping m), 2.61-2.69 (2H, overlapping m), 4.41 (1H, m), 5.38 (2H,s), 6.36 (1H, s), 7.04 (1H, d), 7.16 (1H, d), 7.36 (2H, m), 7.44 (2H,m), 7.58-7.66 (3H, overlapping m), 7.94 (1H, m), 8.10 (1H, s), 8.30-8.36(2H, over- lapping m), 8.41 (1H, m), 8.58 (1H, s), 8.73 (1H, s), 8.80(1H, s), 9.04 (1H, s), 10.58 (1H, s). Route code*: 6 Example 84:

R^(t) 1.63 min (Method 1); m/z 769 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.39 (2H, m), 1.71 (2H, m), 2.06 (2H, m),2.37- 2.57 (5H, overlapping m), 2.74 (2H, m), 3.34-3.50 (3H, overlappingm), 4.53 (1H, m), 5.38 (2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.16 (1H,d), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.67 (3H, overlapping m), 7.95 (1H,m), 8.09 (1H, s), 8.33-8.45 (3H, over- lapping m), 8.59 (1H, s), 8.75(1H, s), 8.80 (1H, s), 9.06 (1H, s), 10.59 (1H, s). Route code*: 6Example 85:

R^(t) 1.73 min (Method 1): m/z 783 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.00-1.18 (6H, overlapping m), 1.27 (9H, s), 1.64 (2H, m),2.30-2.85 (7H, over- lapping m), 3.35-3.75 (4H, overlapping m), 5.39(2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.17 (1H, d), 7.36 (2H, m), 7.44(2H, m), 7.58-7.67 (3H, overlapping m), 7.95 (1H, m), 8.09 (1H, s),8.33-8.49 (3H, overlapping m), 8.60 (1H, s), 8.75 (1H, br s), 8.81 (1H,br s), 9.06 (1H, s), 10.59 (1H, s). Route code*: 6 Example 86:

R^(t) 1.67 min (Method 1); m/z 739 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.79 (4H, m), 2.39 (3H, s), 2.55-3.10 (6H,over- lapping m), 3.50 (2H, m), 5.39 (2H, s), 6.35 (1H, s), 7.04 (1H,d), 7.16 (1H, d), 7.36 (2H, m), 7.45 (2H, m), 7.58-7.67 (3H, overlappingm), 7.96 (1H, m), 8.09 (1H, s), 8.35 (1H, d), 8.41 (1H, m), 8.62-8.65(2H, overlapping m), 8.77 (1H, s), 8.83 (1H, s), 9.07 (1H, s), 10.60(1H, s). Route code*: 6 Example 87:

R^(t) 1.64 min (Method 1); m/z 785 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.31-2.53 (9H, over- lapping m), 3.28-3.46(4H, overlapping m), 3.60 (2H, t), 3.82 (1H, m), 4.90 (1H, d), 5.39 (2H,s), 6.36 (1H, s), 7.04 (1H, d), 7.16 (1H, d), 7.36 (2H, m), 7.44 (2H,m), 7.58-7.67 (3H, overlapping m), 7.95 (1H, m), 8.10 (1H, s), 8.35 (1H,d), 8.41 (1H, m), 8.55-8.60 (2H, overlapping m), 8.76 (1H, s), 8.80 (1H,s), 9.05 (1H, s), 10.59 (1H, s). Route code*: 6 Example 88:

R^(t) 1.67 min (Method 1); m/z 739 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.51 (2H, m), 1.64 (2H, m), 2.10-2.60 (10H,overlapping m), 4.01 (1H, m), 5.39 (2H, s), 6.35 (1H, s), 7.04 (1H, m),7.14 (1H, m), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.67 (3H, overlapping m),7.94 (1H, m), 8.09 (1H, s), 8.25 (1H, d), 8.34 (1H, d), 8.41 (1H, m),8.58 (1H, s), 8.75 (1H, s), 8.80 (1H, s), 9.05 (1H, s), 10.59 (1H, s).Route code*: 6 Example 89:

R^(t) 1.64 min (Method 1); m/z 711 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.31 (3H, s), 2.39 (3H, s), 3.16 (2H, t), 3.61(2H, t), 4.50 (1H, m), 5.39 (2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.17(1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.57- 7.67 (3H, overlapping m),7.95 (1H, m), 8.11 (1H, s), 8.35 (1H, d), 8.41 (1H, m), 8.60 (1H, s),8.73 (1H, s), 8.81 (1H, s), 8.89 (1H, s), 9.06 (1H, s), 10.60 (1H, s).Route code*: 6 Example 90:

R^(t) 1.70 min (Method 1); m/z 750 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.26 (3H, s), 2.39 (3H, s), 3.57 (2H, m), 4.07(2H, t), 5.39 (2H, s), 6.36 (1H, s), 6.69 (1H, s), 7.00 (1H, s), 7.04(1H, d), 7.16 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.67 (3H,overlapping m), 7.93 (1H, m), 8.10 (1H, s), 8.35 (1H, d), 8.41 (1H, m),8.62 (1H, s), 8.72-8.78 (2H, overlapping m), 8.83 (1H, s), 9.04 (1H, s),10.62 (1H, s). Route code*: 6 Example 91:

R^(t) 1.73 min (Method 1): m/z 812 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.37-2.43 (9H, over- lapping m), 3.30-3.45(6H, overlapping m), 3.59 (3H, s), 5.38 (2H, s), 6.36 (1H, s), 7.04 (1H,d), 7.16 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.68 (3H, overlappingm), 7.94 (1H, m), 8.09 (1H, s), 8.35 (1H, d), 8.41 (1H, m), 8.49 (1H,t), 8.60 (1H, s), 8.75 (1H, s), 8.81 (1H, s), 9.05 (1H, s), 10.60 (1H,s). Route code*: 6 Example 92:

R^(t) 1.75 min (Method 1); m/z 783 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.41 (2H, m), 1.83 (2H, m), 2.11 (2H, m), 2.39(3H, s), 2.45 (2H, m), 2.70 (2H, m), 3.16 (1H, m), 3.22 (3H, s), 3.39(2H, m), 5.38 (2H, s), 6.36 (1H, s), 7.04 (1H, d), 7.16 (1H, d), 7.36(2H, m), 7.44 (2H, m), 7.58- 7.68 (3H, overlapping m), 7.94 (1H, m),8.09 (1H, s), 8.35 (1H, d), 8.39-8.47 (2H, overlapping m), 8.60 (1H, s),8.74 (1H, s), 8.81 (1H, s), 9.05 (1H, s), 10.61 (1H, s). Route code*: 6Example 93:

Rt 1.77 min (Method 1); m/z 797 (M + H)⁺ (ES+); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 2.32-2.57 (7H, over- lapping m), 3.15 (1H, m),3.51-3.59 (5H, overlapping m), 3.70 (1H, m), 3.90-4.00 (2H, overlappingm), 4.53 (1H, m), 5.39 (2H, s), 6.36 (1H, s), 7.04 (1H, d), 7.17 (1H,d), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.67 (3H, over- lapping m), 7.62(1H, m), 8.11 (1H, s), 8.35 (1H, d), 8.41 (1H, m), 8.60 (1H, s), 8.75(1H, s), 8.79 (1H, s), 8.81 (1H, s), 9.06 (1H, s), 10.61 (1H, s). Routecode*: 6 Example 94:

R^(t) 1.75 min (Method 1); m/z 789 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.88-2.02 (4H, over- lapping m), 2.40 (3H, s),2.54-2.60 (6H, overlapping m), 3.43 (2H, q), 5.39 (2H, s), 6.36 (1H, s),7.04 (1H, d), 7.17 (1H, dd), 7.36 (2H, m), 7.46 (2H, m), 7.56-7.71 (3H,overlapping m), 7.95 (1H, m), 8.10 (1H, s), 8.35 (1H, d), 8.41 (1H, m),8.48 (1H, t), 8.65 (1H, s), 8.76 (1H, d), 8.82 (1H, s), 9.06 (1H, d),10.59 (1H, s). Route code*: 7 Example 95:

R^(t) 1.64 min (Method 1); m/z 769 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.07 (1H, m), 1.27 (9H, s), 1.42 (1H, m), 1.62 (1H, m), 1.79(2H, t), 1.89 (1H, m), 2.39 (3H, s), 2.69 (1H, m), 2.86 (1H, m),3.21-3.53 (5H, over- lapping m), 4.59 (1H, s), 5.38 (2H, s), 6.35 (1H,s), 7.04 (1H, d), 7.16 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.54- 7.69(3H, overlapping m), 7.94 (1H, m), 8.09 (1H, s), 8.35 (1H, dd),8.38-8.47 (2H, overlapping m), 8.63 (1H, s), 8.75 (1H, d), 8.83 (1H, s),9.05 (1H, d), 10.58 (1H, s). Route code*: 7 Example 96:

R^(t) 1.71 min (Method 1); m/z 771 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.62-1.95 (3H, over- lapping m), 2.30-2.42(4H, overlapping m), 2.55 (3H, overlapping m), 3.41 (2H, q), 4.68 (1H,m), 5.39 (2H, s), 6.36 (1H, s), 7.05 (1H, d), 7.17 (1H, dd), 7.37 (2H,m), 7.45 (2H, m), 7.57-7.69 (3H, overlapping m), 7.95 (1H, m), 8.10 (1H,s), 8.36 (1H, dd), 8.43 (2H, m), 8.63 (1H, s), 8.76 (1H, d), 8.84 (1H,s), 9.06 (1H, d), 10.59 (1H, s). Missing 3H, obscured by the DMSOsolvent peak at 2.5 ppm. Route code*: 7 Example 97:

R^(t) 1.65 min (Method 1); m/z 755 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.56 (1H, m), 1.98 (1H, m), 2.32-2.38 (2H,over- lapping m), 2.40 (3H, s), 2.55- 2.64 (3H, overlapping m), 2.77(1H, m), 3.40 (2H, q), 4.21 (1H, d), 4.70 (1H, d), 5.39 (2H, s), 6.36(1H, s), 7.05 (1H, d), 7.17 (1H, dd), 7.37 (2H, m), 7.45 (2H, m),7.56-7.74 (3H, overlapping m), 7.95 (1H, m), 8.10 (1H, s), 8.35 (1H, d),8.39-8.51 (2H, overlapping m), 8.60 (1H, s), 8.76 (1H, d), 8.81 (1H, s),9.06 (1H, d), 10.59 (1H, s). Route code*: 7 Example 98:

R^(t) 1.70 min (Method 1); m/z 769 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.65 (1H, m), 1.97 (1H, m), 2.40 (3H, s), 2.46(1H, m), 2.53-2.65 (3H, over- lapping m), 2.73 (1H, dd), 3.17 (3H, s),3.40 (2H, q), 3.87 (1H, m), 5.39 (2H, s), 6.36 (1H, s), 7.04 (1H, d),7.16 (1H, dd), 7.37 (2H, m), 7.45 (2H, m), 7.56-7.68 (3H, overlappingm), 7.95 (1H, m), 8.11 (1H, s), 8.35 (1H, dd), 8.42 (1H, m), 8.47 (1H,m), 8.67 (1H, s), 8.75 (1H, d), 8.87 (1H, s), 9.06 (1H, d), 10.61 (1H,s). 4H missing; obscured by the DMSO solvent peak at 2.5 ppm. Routecode*: 7 Example 99:

R^(t) 1.60 min (Method 1); m/z 783 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.40 (2H, m), 1.72- 1.88 (3H, overlapping m),2.58-2.91 (7H, overlapping m), 3.19-3.39 (5H, over- lapping m), 4.50(2H, s), 5.38 (2H, s), 6.36 (1H, s), 7.03 (1H, d), 7.16 (1H, d), 7.36(1H, m), 7.48-7.65 (5H, overlapping m), 7.97 (1H, m), 8.08 (1H, s), 8.35(1H, d), 8.40 (1H, m), 8.69-8.74 (2H, overlapping m), 8.76 (1H, s), 8.85(1H, s), 9.07 (1H, s), 9.47 (1H, s), 10.58 (1H, s). Route code*: 6Example 100:

R^(t) 1.70 min (Method 1); m/z 757 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.90 (1H, m), 2.12 (1H, m), 2.37 (2H, m), 2.40(3H, s), 2.59-2.66 (2H, over- lapping m), 2.79-2.94 (2H, overlapping m),3.42 (2H, q), 5.20 (1H, m), 5.39 (2H, s), 6.36 (1H, s), 7.05 (1H, d),7.17 (1H, d), 7.37 (2H, m), 7.45 (2H, m), 7.59-7.67 (3H, overlapping m),7.95 (1H, m), 8.10 (1H, s), 8.35 (1H, m), 8.42 (1H, m), 8.49 (1H, m),8.59 (1H, s), 8.76 (1H, d), 8.80 (1H, s), 9.06 (1H, d), 10.59 (1H, s).Route code*: 7 Example 101:

R^(t) 1.72 min (Method 1); m/z 771 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.28 (9H, s), 1.39-1.59 (2H, over- lapping m), 1.65-1.92(2H, overlapping m), 2.31 (1H, m), 2.40 (3H, s), 2.80 (1H, m), 3.42 (2H,q), 4.62 (1H, m), 5.39 (2H, s), 6.35 (1H, s), 7.04 (1H, d), 7.16 (1H,dd), 7.36 (2H, m), 7.45 (2H, m), 7.55- 7.71 (3H, overlapping m), 7.96(1H, m), 8.10 (1H, s), 8.35 (1H, m), 8.38-8.52 (3H, overlapping m),8.67-8.81 (2H, overlapping m), 8.95 (1H, s), 9.06 (1H, d), 10.59 (1H,s). Missing 3H, obscured by the DMSO solvent peak at 2.5 ppm Routecode*: 7 Example 102:

R^(t) 1.66 min (Method 1); m/z 796 (M + H)⁺ (ES⁺); ¹H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.98 (3H, s), 2.35- 2.54 (9H, overlapping m),3.38-3.47 (6H, overlapping m), 5.39 (2H, s), 6.36 (1H, s), 7.04 (1H, d),7.16 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.67 (3H, overlapping m),7.94 (1H, m), 8.09 (1H, s), 8.35 (1H, d), 8.38 (1H, m), 8.50 (1H, t),8.60 (1H, s), 8.75 (1H, s), 8.81 (1H, s), 9.05 (1H, s), 10.61 (1H, s).Route code*: 6 Example 103:

Rt 1.64 min (Method 1); m/z 769 (M + H)⁺ (ES+); 1H NMR (400 MHz,DMSO-d₆) δ: 1.27 (9H, s), 1.60-1.78 (4H, over- lapping m), 2.08 (2H, m),2.38- 2.44 (5H, overlapping m), 2.89 (2H, m), 3.50 (2H, t), 3.79 (1H,m), 4.45 (1H, m), 5.38 (2H, s), 6.36 (1H, s), 7.04 (1H, d), 7.15 (1H,d), 7.36 (2H, m), 7.44 (2H, m), 7.57-7.67 (3H, overlapping m), 7.94 (1H,m), 8.10 (1H, s), 8.33-8.43 (3H, overlapping m), 8.63 (1H, s), 8.74 (1H,s), 8.84 (1H, s), 9.06 (1H, s), 10.59 (1H, s). Route code*: 6 Example104:

1-(3-(tert-butyl)-1-(4- methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethyl- amino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.92 min (Method 1);m/z 658 (M + H)⁺ (ES⁺). Route code*: 3 Example 105:

1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-methoxypyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.06 min (Method 1); m/z 629 (M +H)⁺ (ES⁺). Route code*: 1 Example 106:

1-(4-((2-((6-aminopyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)- 3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea R^(t) 1.83 min (Method 1); m/z 614 (M + H)⁺ (ES⁺).Route code*: 3 Example 107:

N-(6-((4-(((4-(3-(3- (tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1- yl)oxy)methyl)pyridin-2-yl)amino)pyrazin-2-yl)-2- methoxyacetamide R^(t) 1.94 min (Method 1);m/z 686 (M + H)⁺ (ES⁺). Route code*: 3 Example 108:

1-(3-(tert-butyl)-1-(4- methoxyphenyl)-1H-pyrazol- 5-yl)-3-(4-((2-((6-methoxypyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.25 min (Method 1); m/z 645 (M + H)⁺ (ES⁺). Route code*: 1Example 109:

1-(3-(tert-butyl)-1-(5- methylthiophen-2-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6- methoxypyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.39 min (Method 1); m/z 635 (M +H)⁺ (ES⁺). Route code*: 1 Example 110:

1-(3-(tert-butyl)-1-(4- (hydroxymethyl)phenyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-methoxypyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.96 min (Method 1); m/z 645 (M +H)⁺ (ES⁺). Route code*: 1 Example 111:

1-(3-(tert-butyl)-1-(5- methylthiophen-2-yl)-1H- pyrazol-5-yl)-3-(4-((2-((6-(dimethylamino) pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.05 min (Method 1); m/z 648 (M + H)⁺ (ES⁺).Route code*: 1 Example 112:

1-(3-(tert-butyl)-1-(5- methylthiophen-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6- (dimethylamino)pyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea R^(t) 2.03 min(Method 1); m/z 648 (M + H)⁺ (ES⁺). Route code*: 1 Example 113:

1-(3-(tert-butyl)-1-(5- methylthiophen-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((6- methoxypyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.38 min (Method 1); m/z 635 (M +H)⁺ (ES⁺). Route code*: 1 Example 114:

1-(3-(tert-butyl)-1-(4- (hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((6-(dimethylamino) pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthaien-1-yl)urea R^(t) 1.75 min (Method 1);m/z 658 (M + H)⁺ (ES⁺). Route code*: 1 Example 115:

1-(3-(tert-butyl)-1-(4- hydroxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(dimethyl- amino)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.79 min (Method 1);m/z 644 (M + H)⁺ (ES⁺). Route code*: 1 Example 116:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-ethoxypyrazin-2-yl) amino)pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.50 min (Method 1); m/z 643 (M + H)⁺ (ES⁺). Route code*: 8Example 117:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(isopropylamino)pyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.05 min (Method 1); m/z 656 (M +H)⁺ (ES⁺). Route code*: 8 Example 118:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-morpholinopyrazin-2- yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl)urea R^(t) min 2.11 (Method 1); m/z 684 (M + H)⁺ (ES⁺). Route code*: 8Example 119:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(cyclopropylamino) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.98 min (Method 1); m/z 654(M + H)⁺ (ES⁺). Route code*: 8 Example 120:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(methylamino)pyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.95 min (Method 1); m/z 628 (M +H)⁺ (ES⁺). Route code*: 8 Example 121:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(2-hydroxyethoxy) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.05 min (Method 1); m/z 659(M + H)⁺ (ES⁺). Route code*: 8 Example 122:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-isobutoxypyrazin-2- yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl)urea R^(t) 2.78 min (Method 1); m/z 671 (M + H)⁺ (ES⁺). Route code*: 8Example 123:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(3-hydroxyazetidin-1-yl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.86 min (Method 1); m/z 670(M + H)⁺ (ES⁺). Route code*: 8 Example 124:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1- yl)oxy)methyl)pyridin-2-yl)amino)-N-(2-isopropoxy- ethyl)pyrazine-2- carboxamide R^(t) 2.48 min(Method 1); m/z 728 (M + H)⁺ (ES⁺). Route code*: 2 Example 125:

N-(2-(tert-butoxy)ethyl)-5-((4- (((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido) naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)pyrazine- 2-carboxamide R^(t) 2.38 min (Method 1);m/z 742 (M + H)⁺ (ES⁺). Route code*: 2 Example 126:

(S)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)- 3-(4-((2-((5-(3-hydroxypyrrolidine-1- carbonyl)pyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1- yl)urea R^(t) 1.66 min (Method 1); m/z 712 (M +H)⁺ (ES⁺). Route code*: 2 Example 127:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-hydroxypiperidine-1- carbonyl)pyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.93 min (Method 1); m/z 726 (M +H)⁺ (ES⁺). Route code*: 2 Example 128:

1-(4-((2-((5-(azetidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H- pyrazol-5-yl)urea R^(t) 2.20 min (Method1); m/z 682 (M + H)⁺ (ES⁺). Route code*: 2 Example 129:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-ethyl-6-methylpyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.80 min (Method 2); m/z 641 (M +H)⁺ (ES⁺). Route code*: 1 Example 130:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6,7-dihydro-5H-cyclopenta [b]pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.68 min (Method 2); m/z 639 (M + H)⁺ (ES⁺).Route code*: 1 Example 131:

1-(3-(tert-butyl)-1-(3- isopropylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.74 min (Method 2); m/z 627 (M +H)⁺ (ES⁺). Route code*: 1 Example 132:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(4-methoxy-3-methyl-phenyl)-1H-pyrazol-5-yl) ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)- N-(2-methoxyethyl)pyrazine- 2-carboxamideR^(t) 2.24 min (Method 1); m/z 365.5 (M + 2H)²⁺ (ES⁺). Route code*: 2Example 133:

1-(3-(tert-butyl)-1-(4- methoxy-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea R^(t) 1.79 min(Method 1); m/z 659 (M + H)⁺ (ES⁺). Route code*: 1 Example 134:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl) amino)-N-(3-hydroxy-propyl)pyrazine-2- carboxamide R^(t) 1.87 min (Method 1); m/z 700 (M +H)⁺ (ES⁺). Route code*: 2 Example 135:

1-(3-(tert-butyl)-1-(4- methoxy-3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea R^(t) 1.99 min(Method 1); m/z 657 (M + H)⁺ (ES⁺). Route code*: 1 Example 136:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methylpiperazine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.62 min (Method1); m/z 725 (M + H)⁺ (ES⁺). Route code*: 2 Example 137:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(piperidine-1-carbonyl) pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.22 min (Method 1); m/z 710 (M + H)⁺ (ES⁺).Route code*: 2 Example 138:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5,6,7,8-tetrahydro- quinoxalin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.78 min (Method 2); m/z 653 (M + H)⁺ (ES⁺).Route code*: 1 Example 139:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5,6-diethylpyrazin-2-yl) amino)pyridin-4-yl) methoxy)naphthalen-1-yl)urea R^(t) 2.92 min (Method 2); m/z 655 (M + H)⁺ (ES⁺). Route code*: 1Example 140:

1-(3-(tert-butyl)-1-(4-methoxy- 3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6- ethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.15 min (Method 1); m/z 657 (M + H)⁺ (ES⁺).Route code*: 1 Example 141:

1-(3-(tert-butyl)-1-(m-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.73 min (Method 2); m/z 627 (M + H)⁺ (ES⁺). Route code*: 1Example 142:

1-(3-(tert-butyl)-1-(3- methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.48 min (Method 2); m/z 615 (M +H)⁺ (ES⁺). Route code*: 1 Example 143:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-ethyl-5-methylpyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.79 min (Method 2); m/z 641 (M +H)⁺ (ES⁺). Route code*: 1 Example 144:

1-(3-(tert-butyl)-1-(3,4- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6- ethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.35 min (Method 1); m/z 641 (M + H)⁺ (ES⁺).Route code*: 1 Example 145:

1-(3-(tert-butyl)-1-(3,4- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6- cyclopropylpyrazin-2- yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.53 min (Method 1); m/z 653 (M +H)⁺ (ES⁺). Route code*: 1 Example 146:

1-(3-(tert-butyl)-1-(3,4- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6- dimethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.18 min (Method 1); m/z 641 (M + H)⁺ (ES⁺).Route code*: 1 Example 147:

1-(3-(tert-butyl)-1-(3,4- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (hydroxymethyl)pyrazin-2- yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.95 min (Method 1); m/z 643 (M +H)⁺ (ES⁺). Route code*: 1 Example 148:

1-(3-(tert-butyl)-1-(3-fluoro- 4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.87 min (Method 1); m/z 633(M + H)⁺ (ES⁺). Route code*: 1 Example 149:

1-(3-(tert-butyl)-1-(4- (methylthio)phenyl)-1H- pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino) pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t)1.97 min (Method 1); m/z 631 (M + H)⁺ (ES⁺). Route code*: 1 Example 150:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropyl-5-methyl- pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.82 min (Method 2); m/z 653 (M + H)⁺ (ES⁺).Route code*: 1 Example 151:

1-(3-(tert-butyl)-1-(3,4- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5- ethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.05 min (Method 1); m/z 641 (M + H)⁺ (ES⁺).Route code*: 1 Example 152:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl) pyrazine-2-carboxamide R^(t) 2.56 min (Method2); m/z 700 (M + H)⁺ (ES⁺). Route code*: 2 Example 153:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(3-methoxypropyl) pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.09 min (Method 1): m/z 671 (M + H)⁺ (ES⁺).Route code*: 1 Example 154:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(2-methoxyethyl) pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.06 min (Method 1): m/z 657 (M + H)⁺ (ES⁺).Route code*: 1 Example 155:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(3-hydroxypropyl) pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 1.91 min (Method 1): m/z 657 (M + H)⁺ (ES⁺).Route code*: 1 Example 156:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl)ureido) naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)-N-2- methoxyethyl)pyrazine-2- carboxamide R^(t) 2.28min (Method 1); m/z 714 (M + H)⁺ (ES⁺). Route code*: 2 Example 157:

1-(3-(tert-butyl)-1-(4-(2- methoxyethoxy)-3-methyl-phenyl)-1H-pyrazol-5-yl)- 3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.97 min (Method 1): m/z 673 (M +H)⁺ (ES⁺). Route code*: 1 Example 158:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(3-methoxyprop-1-yn-1- yl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.38 min (Method 1): m/z 667 (M + H)⁺ (ES⁺).Route code*: 1 Example 159:

1-(3-(tert-butyl)-1-(m-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-ethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.73 min (Method 2); m/z 627 (M + H)⁺ (ES⁺). Route code*: 1Example 160:

1-(3-(tert-butyl)-1-(m-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-cyclopropylpyrazin-2- yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.75 min (Method 2); m/z 639 (M +H)⁺ (ES⁺). Route code*: 1 Example 161:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(tetrahydro-2H-pyran-4- yl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.61 min (Method 2); m/z 683 (M + H)⁺ (ES⁺).Route code*: 1 Example 162:

(R)-1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypyrrolidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.94 min (Method 1):m/z 710 (M − H)⁻ (ES⁻). Route code*: 1 Example 163:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxyazetidine-1- carbonyl)pyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.19 min (Method 1); m/z 712 (M +H)⁺ (ES⁺). Route code*: 1 Example 164:

1-(3-(tert-butyl)-1-(4- ethylphenyl)-1H-pyrazol-5- yl)-3-(4-((2-((5-(hydroxymethyl)pyrazin-2- yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.92 min (Method 1); m/z 641 (M −H)⁻ (ES⁻). Route code*: 1 Example 165:

1-(3-(tert-butyl)-1-(3-ethyl- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl) methoxy)naphthalen-1-yl) ureaR^(t) 2.07 min (Method 1); m/z 613 (M + H)⁺ (ES⁺). Route code*: 1Example 166:

1-(3-(tert-butyl)-1-(3- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.89 min (Method 1); m/z 629(M + H)⁺ (ES⁺). Route code*: 1 Example 167:

1-(3-(tert-butyl)-1-(3- fluoro-4-methylphenyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl) amino)pyridin-4-yl) methoxy)naphthalen-1-yl)urea R^(t) 2.25 min (Method 1); m/z 323 (M + 2H)²⁺ (ES⁺). Route code*: 1Example 168:

1-(3-(tert-butyl)-1-(3-fluoro- 4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6- ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.12 min (Method 1);m/z 331 (M + 2H)²⁺ (ES⁺). Route code*: 1 Example 169:

1-(3-(tert-butyl)-1-(3- fluorophenyl)-1H-pyrazol- 5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl) amino)pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.67 min (Method 2); m/z 631 (M + H)⁺ (ES⁺). Route code*: 1Example 170:

1-(3-(tert-butyl)-1-(3- methoxyphenyl)-1H-pyrazol- 5-yl)-3-(4-((2-((5,6-dimethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.59 min (Method 2); m/z 643 (M + H)⁺ (ES⁺). Route code*: 1Example 171:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(2-hydroxyethyl) pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 1.85 min (Method 1); m/z 643 (M + H)⁺ (ES⁺).Route code*: 1 Example 172:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2-yl) amino)pyridin-4-yl) methoxy)naphthalen-1-yl)urea R^(t) 2.28 min (Method 1); m/z 641 (M + H)⁺ (ES⁺). Route code*: 1Example 173:

1-(3-(tert-butyl)-1-(4- ethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.82 min (Method 2); m/z 641 (M +H)⁺ (ES⁺). Route code*: 1 Example 174:

1-(3-(tert-butyl)-1-(3- (hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.70 min (Method 1); m/z 308(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 175:

1-(3-(tert-butyl)-1-(3- chlorophenyl)-1H-pyrazol- 5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.24 min (Method 1); m/z 324 (M + 2H)²⁺ (ES⁺). Route code*: 1Example 176:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-fluoropiperidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.23 min (Method1); m/z 728 (M + H)⁺ (ES⁺). Route code*: 6 Example 177:

1-(3-(tert-butyl)-1-(6- methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (hydroxymethyl)pyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea. R^(t) 1.70 min(Method 1); m/z 646 (M + H)⁺ (ES⁺). Route code*: 1 Example 178:

1-(3-(tert-butyl)-1-(3- methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxy- methyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea. R^(t) 1.77 min (Method 1):m/z 645 (M + H)⁺ (ES⁺). Route code*: 1 Example 179:

1-(3-(tert-butyl)-1-(3-chloro- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethyl- pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.77 min (Method 2); m/z 647(M + H)⁺ (ES⁺). Route code*: 1 Example 180:

1-(3-(tert-butyl)-1-(3,5- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.65 min (Method 2); m/z 613 (M +H)⁺ (ES⁺). Route code*: 1 Example 181:

1-(3-(tert-butyl)-1-(3-fluoro- 5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.62 min (Method 2); m/z 617(M + H)⁺ (ES⁺). Route code*: 1 Example 182:

1-(3-(tert-butyl)-1-(3-fluoro- 4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6- dimethylpyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.88 min (Method 2); m/z 645 (M +H)⁺ (ES⁺). Route code*: 1 Example 183:

1-(3-(tert-butyl)-1-(4-ethoxy- 3-fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.03 min (Method 1); m/z 324 (M +2H)²⁺ (ES⁺). Route code*: 1 Example 184:

1-(3-(tert-butyl)-1-(3- ethoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin- 2-ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.01 min (Method 1); m/z 315 (M +2H)²⁺ (ES⁺). Route code*: 1 Example 185:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methylpiperidine-1- carbonyl)pyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.45 min (Method 1); m/z 724 (M +H)⁺ (ES⁺). Route code*: 6 Example 186:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(3-methoxypropyl) pyrazine-2-carboxamide R^(t) 2.26 min (Method1): m/z 714 (M + H)⁺ (ES⁺). Route code*: 6 Example 187:

1-(3-(tert-butyl)-1-(4- fluorophenyl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.43 min (Method 2); m/z 603 (M +H)⁺ (ES⁺). Route code*: 1 Example 188:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypropyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.07 min (Method 1); m/z 671(M + H)⁺ (ES⁺). Route code*: 1 Example 189:

1-(3-(tert-butyl)-1-(3- methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propyl- pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.25 min (Method 1); m/z 657(M + H)⁺ (ES⁺). Route code*: 1 Example 190:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(methoxymethyl)pyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.05 min (Method 1); m/z 643 (M +H)⁺ (ES⁺). Route code*: 1 Example 191:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) methyl)pyridin-2-yl)amino)-N-ethylpyrazine-2- carboxamide R^(t) 2.27 min (Method 1); m/z 670 (M +H)⁺ (ES⁺). Route code*: 6 Example 192:

5-((4-(((4-(3-(3-(tert-butyl)-1- (p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) methyl)pyridin-2-yl)amino)-N-propylpyrazine-2- carboxamide R^(t) 2.39 min (Method 1); m/z 684 (M +H)⁺ (ES⁺). Route code*: 6 Example 193:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(3-fluoroazetidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.27 min (Method1); m/z 700 (M + H)⁺ (ES⁺). Route code*: 6 Example 194:

1-(3-(tert-butyl)-1-(3-fluoro- 4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propyl- pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.39 min (Method 1); m/z 659(M + H)⁺ (ES⁺). Route code*: 1 Example 195:

1-(3-(tert-butyl)-1-(m-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(methoxymethyl)pyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.96 min (Method 1); m/z 643 (M +H)⁺ (ES⁺). Route code*: 1 Example 196:

1-(3-(tert-butyl)-1-(3- methoxy-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.00 min (Method 1); m/z 315(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 197:

1-(3-(tert-butyl)-1-(4-ethoxy- 3-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.09 min (Method 1); m/z 322(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 198:

1-(3-(tert-butyl)-1-(6- methylpyridin-3-yl)-1H- pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)1.60 min (Method 1); m/z 600 (M + H)⁺ (ES⁺). Route code*: 1 Example 199:

(R)-1-(3-(tert-butyl)-1-(m- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxy- pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)2.19 min (Method 1): m/z 726 (M + H)⁺ (ES⁺). Route code*: 6 Example 200:

(S)-1-(3-(tert-butyl)-1-(m- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxy- pyrrolidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.19 min (Method 1);m/z 726 (M + H)⁺ (ES⁺). Route code*: 6 Example 201:

1-(3-(tert-butyl)-1-(m-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2-yl) amino)pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.33 min (Method 1); m/z 641 (M + H)⁺ (ES⁺). Route code*: 1Example 202:

1-(3-(tert-butyl)-1-(3- fluorophenyl)-1H-pyrazol- 5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl) pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.24 min (Method 1); m/z 700 (M + H)⁺ (ES⁺).Route code*: 2 Example 203:

1-(3-(tert-butyl)-1-(3- fluorophenyl)-1H-pyrazol- 5-yl)-3-(4-((2-((5-(methoxymethyl)pyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 1.96 min (Method 1); m/z 647 (M +H)⁺ (ES⁺). Route code*: 1 Example 204:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-methylpyrazine- 2-carboxamide R^(t) 1.76 min (Method 1); m/z656 (M + H)⁺ (ES⁺). Route code*: 2 Example 205:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(2-methoxyethyl)- N-methylpyrazine-2- carboxamide R^(t) 2.05min (Method 1); m/z 714 (M + H)⁺ (ES⁺). Route code*: 6 Example 206:

1-(3-(tert-butyl)-1-(m-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methoxypiperidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.18 min (Method 1);m/z 740 (M + H)⁺ (ES⁺). Route code*: 6 Example 207:

1-(3-(tert-butyl)-1-(6- methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6- dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.50 min (Method2): m/z 644 (M + H)⁺ (ES⁺). Route code*: 1 Example 208:

1-(3-(tert-butyl)-1-(3- methoxy-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5,6-dimethylpyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea R^(t) 2.71 min(Method 2); m/z 657 (M + H)⁺ (ES⁺). Route code*: 1 Example 209:

2-(6-((4-(((4-(3-(3-(tert- butyl)-1-(p-tolyl)-1H- pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) methyl)pyridin-2-yl)amino) pyrazin-2-yl)-N-(2-methoxyethyl)acetamide R^(t) 1.86 min (Method 1); m/z 714 (M + H)⁺(ES⁺). Route code*: 5a Example 210:

1-(3-(tert-butyl)-1-(4- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.11 min (Method1); m/z 329 (M + 2H)²⁺ (ES⁺). Route code*: 1 Example 211:

1-(3-(tert-butyl)-1-(3-fluoro- 5-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6- ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.24 min (Method 1);m/z 331 (M + 2H)²⁺ (ES⁺). Route code*: 1 Example 212:

1-(3-(tert-butyl)-1-(3,5- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethyl- pyrazin-2-yl)amino) pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.42 min (Method 1); m/z 321 (M + 2H)²⁺(ES⁺). Route code*: 1 Example 213:

1-(3-(tert-butyl)-1-(4-fluoro- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.15 min (Method 1); m/z 316 (M + 2H)²⁺(ES⁺). Route code*: 1 Example 214:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-((2S,6R)-2,6-dimethyl- morpholine-4-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.31 min (Method 1);m/z 740 (M + H)⁺ (ES⁺). Route code*: 1 Example 215:

1-(3-(tert-butyl)-1-(4-fluoro- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.21 min (Method1); m/z 700 (M + H)⁺ (ES⁺). Route code*: 2 Example 216:

1-(3-(tert-butyl)-1-(3- methoxyphenyl)-1H- pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1- yl)urea R^(t) 2.31 min (Method 1); m/z 712(M + H)⁺ (ES⁺). Route code*: 2 Example 217:

1-(3-(tert-butyl)-1-(4- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t)2.28 min (Method 1); m/z 726 (M + H)⁺ (ES⁺). Route code*: 2 Example 218:

1-(3-(tert-butyl)-1-(3,5- dimethylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (pyrrolidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.74 min (Method 2);m/z 710 (M + H)⁺ (ES⁺). Route code*: 6 Example 219:

1-(3-(tert-butyl)-1-(6- methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (pyrrolidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.04 min (Method 1);m/z 713 (M + H)⁺ (ES⁺). Route code*: 6 Example 220:

1-(3-(tert-butyl)-1-(3-fluoro- 5-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.04 min (Method 1); m/z 317(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 221:

1-(3-(tert-butyl)-1-(3- methoxy-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((6-ethylpyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1- yl)urea R^(t) 2.22 min (Method 1); m/z 329 (M +2H)²⁺ (ES⁺). Route code*: 1 Example 222:

1-(3-(tert-butyl)-1-(3- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.13 min (Method 1);m/z 329 (M + 2H)²⁺ (ES⁺). Route code*: 1 Example 223:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) methyl)pyridin-2-yl)amino)-N-(3-hydroxypropyl)-N- methylpyrazine-2- carboxamide R^(t) 1.98 min(Method 1); m/z 714 (M + H)⁺ (ES⁺). Route code*: 6 Example 224:

1-(3-(tert-butyl)-1-(m-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxyazetidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.22 min (Method1); m/z 712 (M + H)⁺ (ES⁺). Route code*: 6 Example 225:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(3-(methoxymethyl) azetidine-l-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.29 min (Method 1);m/z 726 (M + H)⁺ (ES⁺). Route code*: 6 Example 226:

1-(3-(tert-butyl)-1-(3- methoxy-4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 2.63 min (Method 2); m/z 726 (M + H)⁺ (ES⁺). Route code*: 6Example 227:

1-(3-(tert-butyl)-1-(3- methoxy-5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(pyrrolidine-1-carbonyl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t)2.28 min (Method 1); m/z 726 (M + H)⁺ (ES⁺). Route code*: 6 Example 228:

1-(3-(tert-butyl)-1-(3-fluoro- 4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)2.30 min (Method 1); m/z 730 (M + H)⁺ (ES⁺). Route code*: 2 Example 229:

1-(3-(tert-butyl)-1-(4-ethyl- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.35 min (Method 1);m/z 710 (M + H)⁺ (ES⁺). Route code*: 2 Example 230:

1-(3-(tert-butyl)-1-(3-ethyl- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(pyrrolidine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.35 min (Method 1);m/z 710 (M + H)⁺ (ES⁺). Route code*: 2 Example 231:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(m-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1- yl)oxy)methyl)pyridin-2-yl)amino)-N-(3-hydroxypropyl) pyrazine-2-carboxamide R^(t) 2.09 min (Method1); m/z 700 (M + H)⁺ (ES⁺). Route code*: 6 Example 232:

(S)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypiperidine- 1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.05 min (Method1); m/z 726 (M + H)⁺ (ES⁺). Route code*: 6 Example 233:

(R)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-hydroxypiperidine- 1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.97 min (Method1); m/z 726 (M + H)⁺ (ES⁺). Route code*: 6 Example 234:

1-(3-(tert-butyl)-1-(3-ethyl- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl) amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea R^(t) 2.30 min (Method 1); m/z 321.2 (M + 2H)²⁺(ES⁺). Route code*: 1 Example 235:

1-(3-(tert-butyl)-1-(3-fluoro- 4-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (pyrrolidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.64 min (Method 2): m/z 714(M + H)⁺ (ES⁺). Route code*: 6 Example 236:

1-(3-(tert-butyl)-1-(3-fluoro- 5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (pyrrolidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.71 min (Method 2); m/z 714(M + H)⁺ (ES⁺). Route code*: 6 Example 237:

1-(3-(tert-butyl)-1-(3-(2- hydroxyethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.72 min (Method 1); m/z 629(M + H)⁺ (ES⁺). Route code*: 1 Example 238:

(S)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxypiperidine- 1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.19 min (Method1); m/z 740 (M + H)⁺ (ES⁺). Route code*: 6 Example 239:

(R)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-methoxy- piperidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.19 min (Method 1); m/z 740(M + H)⁺ (ES⁺). Route code*: 6 Example 240:

1-(4-((2-((5-(4-acetyl- piperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)urea R^(t) 2.00 min(Method 1); m/z 753 (M + H)⁺ (ES⁺). Route code*: 6 Example 241:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(5-oxo-1,4-diazepane-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.96 min (Method 1);m/z 739 (M + H)⁺ (ES⁺). Route code*: 6 Example 242:

(S)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-fluoropyrrolidine- 1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.28 min (Method1); m/z 357.5 (M + 2H)²⁺ (ES⁺). Route code*: 6 Example 243:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(1,1-dioxidothiomor- pholine-4-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea R^(t) 2.16 min(Method 1); m/z 380.8 (M + 2H)²⁺ (ES⁺). Route code*: 6 Example 244:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methyl-3-oxopipera- zine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea R^(t) 2.04 min(Method 1); m/z 370.2 (M + 2H)²⁺ (ES⁺). Route code*: 6 Example 245:

(R)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-fluoropyrrolidine- 1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.24 min (Method1); m/z 357.7 (M + 2H)²⁺ (ES⁺). Route code*: 6 Example 246:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4,4-difluoropiperidine- 1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.40 min (Method1); m/z 373.7 (M + 2H)²⁺ (ES⁺). Route code*: 6 Example 247:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-((3S,4S)-3,4-dihydroxy- pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)1.85 min (Method 1); m/z 728 (M + H)⁺ (ES⁺). Route code*: 6 Example 248:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-((3R,4R)-3,4-dihydroxy- pyrrolidine-1-carbonyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)1.85 min (Method 1); m/z 728 (M + H)⁺ (ES⁺). Route code*: 6 Example 249:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(3-oxopiperazine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.91 min (Method 1);m/z 725 (M + H)⁺ (ES⁺). Route code*: 6 Example 250:

1-(3-(tert-butyl)-1-(3-fluoro- 5-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5- (pyrrolidine-1-carbonyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.66 min (Method 2);m/z 730 (M + H)⁺ (ES⁺). Route code*: 6 Example 251:

1-(3-(tert-butyl)-1-(4-ethyl- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6-dimethylpyrazin- 2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.73 min (Method 2); m/z 641 (M +H)⁺ (ES⁺). Route code*: 1 Example 252:

1-(3-(tert-butyl)-1-(3-fluoro- 4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5,6- dimethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 2.59 min (Method 2);m/z 661 (M + H)⁺ (ES⁺). Route code*: 1 Example 253:

1-(3-(tert-butyl)-1-(3-fluoro- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.83 min (Method 1); m/z 633(M + H)⁺ (ES⁺). Route code*: 1 Example 254:

1-(3-(tert-butyl)-1-(3-fluoro- 5-methylphenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethyl- pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.22 min (Method 1); m/z 323.1(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 255:

1-(3-(tert-butyl)-1-(3-fluoro- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-propylpyrazin-2- yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl) urea R^(t) 2.30 min (Method 1); m/z 645 (M +H)⁺ (ES⁺). Route code*: 1 Example 256:

1-(3-(tert-butyl)-1-(3-chloro- phenyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(hydroxymethyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.91 min (Method 1); m/z 649(M + H)⁺ (ES⁺). Route code*: 1 Example 257:

1-(3-(tert-butyl)-1-(3-(2- methoxyethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- (pyrazin-2-ylamino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 2.00 min (Method 1); m/z 322.2(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 258:

(S)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-(dimethyl- amino)pyrrolidine-1-carbonyl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 1.66 min (Method 1); m/z 739 (M + H)⁺ (ES⁺). Route code*: 6Example 259:

(R)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(3-(dimethylamino) pyrrolidine-1-carbonyl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t)1.65 min (Method 1); m/z 739 (M + H)⁺ (ES⁺). Route code*: 6 Example 260:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) methyl)pyridin-2-yl)amino)-N-(2-(4-methylpiperazin-1- yl)ethyl)pyrazine-2- carboxamide R^(t) 1.63min (Method 1); m/z 768 (M + H)⁺ (ES⁺). Route code*: 6 Example 261:

1-(3-(tert-butyl)-1-(3- ((dimethylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3- (4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.45 min (Method 1);m/z 642 (M + H)⁺ (ES⁺). Route code*: 1 Example 262:

1-(3-(tert-butyl)-1-(3- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(morpholinomethyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)1.62 min (Method 1); m/z 364.7 (M + 2H)²⁺ (ES⁺). Route code*: 1 Example263:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(morpholinomethyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.68 min (Method 1); m/z 349.8(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 264:

1-(3-(tert-butyl)-1-(2- methoxypyridin-4-yl)-1H- pyrazol-5-yl)-3-(4-((2-(pyrazin-2-ylamino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)2.41 min (Method 2); m/z 616 (M + H)⁺ (ES⁺). Route code*: 1 Example 265:

1-(3-(tert-butyl)-1-(2-methyl- pyridin-4-yl)-1H-pyrazol-5-yl)-3-(4-((2-(pyrazin-2- ylamino)pyridin-4-yl) methoxy)naphthalen-1-yl)urea R^(t) 2.26 min (Method 2); m/z 600 (M + H)⁺ (ES⁺). Route code*: 1Example 266:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(2-(1-methyl- piperidin-4-yl)ethyl) pyrazine-2-carboxamideR^(t) 1.71 min (Method 1); m/z 767 (M + H)⁺ (ES⁺). Route code*: 6Example 267:

1-(3-(tert-butyl)-1-(4- ((dimethylamino)methyl)phenyl)-1H-pyrazol-5-yl)-3- (4-((2-(pyrazin-2-ylamino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.45 min (Method 1);m/z 642 (M + H)⁺ (ES⁺). Route code*: 1 Example 268:

5-((4-(((4-(3-(3-(tert-butyl)-1- (p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) methyl)pyridin-2-yl)amino)-N-(2-(dimethylamino)ethyl) pyrazine-2-carboxamide R^(t) 1.66 min (Method1); m/z 713 (M + H)⁺ (ES⁺). Route code*: 6 Example 269:

1-(3-(tert-butyl)-1-(3- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(4-methylpiperazine-1-carbonyl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 1.59 min (Method 1); m/z 755 (M + H)⁺ (ES⁺). Route code*: 6Example 270:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(3-(methoxymethyl)phenyl)-1H-pyrazol-5-yl) ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)amino)- N-(2-morpholinoethyl) pyrazine-2-carboxamideR^(t) 1.64 min (Method 1); m/z 785 (M + H)⁺ (ES⁺). Route code*: 6Example 271:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-ethylpiperazine-1- carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.69 min (Method1); m/z 739 (M + H)⁺ (ES⁺). Route code*: 6 Example 272:

1-(3-tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-(dimethylamino) piperidine-1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl) methoxy)naphthalen-1-yl) urea R^(t) 1.65 min(Method 1); m/z 753 (M + H)⁺ (ES⁺). Route code*: 6 Example 273:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-(2-(dimethylamino) ethyl)piperazine-1-carbonyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)1.58 min (Method 1); m/z 782 (M + H)⁺ (ES⁺). Route code*: 6 Example 274:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-(4-methyl-1,4-diazepane- 1-carbonyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.60 min (Method1); m/z 739 (M + H)⁺ (ES⁺). Route code*: 6 Example 275:

(S)-1-(3-(tert-butyl)-1-(p- tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((5-(octahydropyrrolo [1,2-a]pyrazine-2-carbonyl)pyrazin-2-yl)amino)pyridin- 4-yl)methoxy)naphthalen- 1-yl)urea R^(t)1.64 min (Method 1); m/z 751 (M + H)⁺ (ES⁺). Route code*: 6 Example 276:

1-(3-(tert-butyl)-1-(3- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl) amino)pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 1.60 min (Method 1); m/z 371.3 (M + 2H)²⁺ (ES⁺). Route code*: 1Example 277:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((5-((4-methylpiperazin-1- yl)methyl)pyrazin-2-yl)amino)pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t) 1.66 min (Method1); m/z 356.2 (M + 2H)²⁺ (ES⁺). Route code*: 1 Example 278:

(S)-5-((4-(((4-(3-(3-(tert- butyl)-1-(p-tolyl)-1H- pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl) pyridin-2-yl)amino)-N-(1-morpholinopropan-2-yl) pyrazine-2-carboxamide R^(t) 1.69 min (Method 1);m/z 769 (M + H)⁺ (ES⁺). Route code*: 6 Example 279:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(3-morpholino- propyl)pyrazine-2- carboxamide R^(t) 1.65 min(Method 1); m/z 769 (M + H)⁺ (ES⁺). Route code*: 6 Example 280:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(3-(4-methyl- piperazin-1-yl)propyl) pyrazine-2-carboxamideR^(t) 1.55 min (Method 1); m/z 782 (M + H)⁺ (ES⁺). Route code*: 6Example 281:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(2-methyl-2- morpholinopropyl)pyrazine- 2-carboxamide R^(t)1.73 min (Method 1); m/z 783 (M + H)⁺ (ES⁺). Route code*: 6 Example 282:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(1-(2-methoxy- ethyl)piperidin-4-yl) pyrazine-2-carboxamideR^(t) 1.69 min (Method 1); m/z 783 (M + H)⁺ (ES⁺). Route code*: 6Example 283:

1-(3-(tert-butyl)-1-(3- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(4-ethylpiperazine-1-carbonyl)pyrazin-2-yl) amino)pyridin-4-yl)methoxy) naphthalen-1-yl)ureaR^(t) 1.58 min (Method 1); m/z 769 (M + H)⁺ (ES⁺). Route code*: 6Example 284:

1-(3-(tert-butyl)-1-(3- (methoxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((2- ((5-(4-(dimethylamino) piperidine-1-carbonyl)pyrazin-2-yl)amino) pyridin-4-yl)methoxy) naphthalen-1-yl)urea R^(t)1.56 min (Method 1): m/z 783 (M + H)⁺ (ES⁺). Route code*: 6 Example 285:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(morpholinomethyl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.77 min (Method 1); m/z 349.8(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 286:

1-(3-(tert-butyl)-1-(p-tolyl)- 1H-pyrazol-5-yl)-3-(4-((2-((6-(1-methylpiperidin-4-yl) pyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen- 1-yl)urea R^(t) 1.66 min (Method 1); m/z 349(M + 2H)²⁺ (ES⁺). Route code*: 1 Example 287:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)methyl)pyridin-2-yl)amino)-N-(2-methyl-1- morpholinopropan-2-yl) pyrazine-2-carboxamideR^(t) 1.79 min (Method 1); m/z 783 (M + H)⁺ (ES⁺). Route code*: 6Example 288:

5-((4-(((4-(3-(3-(tert-butyl)- 1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy) methyl)pyridin-2-yl)amino)-N-((1-methyl-1H-imidazol- 2-yl)methyl)pyrazine-2- carboxamide R^(t) 1.69min (Method 1); m/z 736 (M + H)⁺ (ES⁺). Route code*: 6 *Route codes: 1-5are the same as for Examples 10-52 5a: compound (I) prepared by reactionof compound (II) with compound (III); compound (III) prepared bydeprotection of compound (IX); compound (IX) prepared from compound(IX″); compound (IX″) prepared from the methyl ester derivative ofcompound (XIVb) by nitro reduction followed by Boc protection and esterhydrolysis; the alkyl ester derivative of compound (XIVb) prepared byreaction of compound (XI) with an analogue of a compound of formula (V)having R^(2d) = CH₂COOMe. 6: compound (I) prepared by reaction ofcompound (II) with compound (III); compound (III) prepared bydeprotection of compound (IX); compound (IX) prepared from compound(IX′) (carboxylic acid) by amide formation; compound (IX′) (carboxylicacid) prepared from compound (IX′) (carboxylic acid ester) byhydrolysis; compound (IX′) (carboxylic acid ester) prepared by reactionof compound (XVI) with compound (XIII′) (carboxylic acid ester). Thisroute is illustrated in the synthesis of Example 53. 7: compound (I)prepared by transformation of another compound of formula (I). Thisroute is illustrated in the synthesis of Example 54. 8: compound (I)prepared by reaction of compound (IV) with compound (V). Compound (IV)prepared by reaction of compound (II) with compound (X). Compound (X)prepared by reduction of compound (XI). This route is illustrated in thesynthesis of Example 55

BIOLOGICAL EXAMPLES

Experimental Methods for Biological Testing

Enzyme Inhibition Assays

The enzyme inhibitory activities of compounds disclosed herein weredetermined by FRET using synthetic peptides labelled with both donor andacceptor fluorophores (Z-LYTE, Life Technologies, Paisley, UK).

p38 MAPKα Enzyme Inhibition

The inhibitory activities of compounds of the invention against the p38MAPKα isoform (MAPK14: Life Technologies), were evaluated indirectly bydetermining the level of activation/phosphorylation of the targetpeptide of the p38 MAPKα down-stream molecule, MAPKAP-K2. The enzyme (40ng/mL, 2.5 μL) was incubated with the test compound (2.5 μL of either 40μg/mL, 12 μg/mL, 4 μg/mL, 1.2 μg/mL, 0.4 μg/mL, 0.12 μg/mL, 0.04 μg/mL,0.012 μg/mL, 0.004 μg/mL or 0.0012 μg/mL) for 2 h at RT. The FRETpeptides (8 μM, 2.5 μL) and the p38a inactive target MAPKAP-K2 (LifeTechnologies, 2000 ng/mL), and appropriate ATP solution (2.5 μL, 40 μM)were then added to the enzyme/compound mixture and incubated for 1 h atRT. Development reagent (protease, 5 μL) was added for 1 h prior todetection in a fluorescence microplate reader (EnVision, Perkin Elmer,Waltham, Mass., USA).

p38 MAPKγ Enzyme Inhibition

The inhibitory activities of compounds of the invention against p38MAPKγ(MAPK12: Life Technologies), were evaluated by determining the level ofactivation/phosphorylation of the target peptide. The enzyme (800 ng/mL,2.5 μL) was incubated with the test compound (2.5 μL at either 40 μg/mL,12 μg/mL, 4 μg/mL, 1.2 μg/mL, 0.4 μg/mL, 0.12 μg/mL, 0.04 μg/mL, 0.012μg/mL, 0.004 μg/mL or 0.0012 μg/mL) for 2 h at RT. The FRET peptides (8μM, 2.5 μL), and appropriate ATP solution (2.5 μL, 400 μM) were thenadded to the enzymes/compound mixtures and incubated for 1 h at RT.Development reagent (protease, 5 μL) was added for 1 h prior todetection in a fluorescence microplate reader (EnVision, Perkin Elmer).

Hck, c-Src and Syk Enzyme Inhibition

The inhibitory activities of compounds of the invention against Hck,c-Src and Syk enzymes (Life Technologies) were evaluated in a similarfashion to that described hereinabove. The relevant enzyme (1000 ng/mL,1400 ng/mL or 2000 ng/mL respectively, 2.5 μL) was incubated with thetest compound (either 40 μg/mL, 12 μg/mL, 4 μg/mL, 1.2 μg/mL, 0.4 μg/mL,0.12 μg/mL, 0.04 μg/mL, 0.012 μg/mL, 0.004 μg/mL or 0.0012 μg/mL, 2.5 μLeach) for 2 h at RT. The FRET peptides (8 μM, 2.5 μL), and appropriateATP solutions (2.5 μL, 800 μM for c-Src, and 60 μM ATP for HCK and Syk)were then added to the enzyme/compound mixtures and incubated for 1 h atRT. Development reagent (protease, 5 μL) was added for 1 h prior todetection in a fluorescence microplate reader (EnVision, Perkin Elmer).

GSK 3α Enzyme Inhibition

The inhibitory activities compounds of the invention against the GSK 3αenzyme isoform (Life Technologies) were evaluated in a similar fashionto that described hereinabove. The GSK3a protein (500 ng/mL, 2.5 μL) wasincubated with the test compound (2.5 μL at either 40 μg/mL, 12 μg/mL, 4μg/mL, 1.2 μg/mL, 0.4 μg/mL, 0.12 μg/mL, 0.04 μg/mL, 0.012 μg/mL, 0.004μg/mL or 0.0012 μg/mL) for 2 h at RT. The FRET peptide (8 μM, 2.5 μL),which is a phosphorylation target for GSK3α, and ATP (40 μM, 2.5 μL) wasthen added to the enzyme/compound mixture and the resulting mixtureincubated for 1 h at RT. Development reagent (protease, 5 μL) was addedfor 1 h prior to detection in a fluorescence microplate reader(EnVision, Perkin Elmer).

In all cases, the site-specific protease cleaves non-phosphorylatedpeptide only and eliminates the FRET signal. Phosphorylation levels ofeach reaction were calculated using the ratio of coumarin emission(donor) over fluorescein emission (acceptor), for which low ratiosindicate high phosphorylation and high ratios indicate lowphosphorylation levels. The percentage inhibition of each reaction wascalculated relative to non-inhibited control and the 50% inhibitoryconcentration (IC₅₀ value) was then calculated from theconcentration-response curve.

Cellular Assays (Employed in the Examples)

The following cellular assays were employed to assess compounds of thepresent invention and the results are given infra.

LPS-Induced TNFα/IL-8 Release in d-U937 Cells

U937 cells, a human monocytic cell line, were differentiated intomacrophage-type cells by incubation with PMA (100-200 ng/mL) for 48 to72 h. Cells were pre-incubated with final 35 concentrations of testcompound for 2 h and were then stimulated with LPS (0.1 μg/mL; from E.coli: O111:B4, Sigma) for 4 h. The supernatant was collected fordetermination of TNFα and IL-8 concentrations by sandwich ELISA(Duo-set, R&D systems). The inhibition of TNFα production was calculatedas a percentage of that achieved by 10 μg/mL of BIRB-796 at eachconcentration of test compound by comparison against vehicle control.The relative 50% effective concentration (REC₅₀) was determined from theresultant concentration-response curve. The inhibition of IL-8production was calculated at each concentration of test compound bycomparison with vehicle control. The 50% inhibitory concentration (IC₅₀)was determined from the resultant concentration-response curve.

Poly I:C-Induced ICAM-1 Expression in BEAS2B Cells

Poly I:C was used in these studies as a simple, RNA virus mimic. PolyI:C-Oligofectamine mixture (2% Oligofectamine±1 μg/mL Poly I:C, 25 μL;Life Technologies and Invivogen Ltd., San Diego, Calif., respectively)was transfected into BEAS2B cells (human bronchial epithelial cells,ATCC). Cells were pre-incubated with final concentrations of testcompounds for 2 h and the level of ICAM-1 expression on the cell surfacewas determined by cell-based ELISA. At a time point 18 h after poly I:Ctransfection, cells were fixed with 4% formaldehyde in PBS (100 μL) andthen endogenous peroxidase was quenched by the addition of washingbuffer (100 μL, 0.05% Tween in PBS: PBS-Tween) containing 0.1% sodiumazide and 1% hydrogen peroxide. Cells were washed with wash-buffer(3×200 μL). After blocking the wells with 5% milk in PBS-Tween (100 μL)for 1 h, the cells were incubated with anti-human ICAM-1 antibody (50μL; Cell Signaling Technology, Danvers, Mass.) in 1% BSA PBS overnightat 4° C.

The cells were washed with PBS-Tween (3×200 μL) and incubated with thesecondary antibody (100 μL; HRP-conjugated anti-rabbit IgG, Dako Ltd.,Glostrup, Denmark). The cells were then incubated with of substrate (50μL) for 2-20 min, followed by the addition of stop solution (50 μL, 1NH₂SO₄). The ICAM-1 signal was detected by reading the absorbance at 450nm against a reference wavelength of 655 nm using a spectrophotometer.The cells ware then washed with PBS-Tween (3×200 μL) and total cellnumbers in each well were determined by reading absorbance at 595 nmafter Crystal Violet staining (50 μL of a 2% solution in PBS) andelution by 1% SDS solution (100 μL) in PBS. The measured OD 450-655readings were corrected for cell number by dividing with the OD595reading in each well. The inhibition of ICAM-1 expression was calculatedat each concentration of test compound by comparison with vehiclecontrol. The 50% inhibitory concentration (IC₅₀) was determined from theresultant concentration-response curve.

Cell Mitosis Assay

Peripheral blood mononucleocytes (PBMCs) from healthy subjects wereseparated from whole blood (Quintiles, London, UK) using a densitygradient (Histopaquee-1077, Sigma-Aldrich, Poole, UK). The PBMCs (3million cells per sample) were subsequently treated with 2% PHA(Sigma-Aldrich, Poole, UK) for 48 h, followed by a 20 h exposure tovarying concentrations of test compounds. At 2 h before collection,PBMCs were treated with demecolcine (0.1 μg/mL; Life Technologies,Paisley, UK,) to arrest cells in metaphase. To observe mitotic cells,PBMCs were permeabilised and fixed by adding Intraprep (50 μL; BeckmanCoulter, France), and stained with anti-phospho-histone 3 (0.26 ng/L;#9701; Cell Signalling) and propidium iodide (1 mg/mL; Sigma-Aldrich aspreviously described (Muehlbauer P. A. and Schuler M. J., MutationResearch, 2003, 537:117-130). Fluorescence was observed using an ATTUNEflow cytometer (Life Technologies), gating for lymphocytes. Thepercentage inhibition of mitosis was calculated for each treatmentrelative to vehicle (0.5% DMSO) treatment.

The Effect of Test Compounds on Cell Viability: MTT Assay

Differentiated U937 cells were pre-incubated with each test compound(final concentration 10 μg/mL in 200 μL media indicated below) under twoprotocols: the first for 4 h in 5% FCS RPMI1640 media and the second in10% FCS RPMI1640 media for 24 h. The supernatant was replaced with newmedia (200 μL) and MTT stock solution (10 μL, 5 mg/mL) was added to eachwell. After incubation for 1 h the media were removed, DMSO (200 μL) wasadded to each well and the plates were shaken lightly for 1 h prior toreading the absorbance at 550 nm. The percentage loss of cell viabilitywas calculated for each well relative to vehicle (0.5% DMSO) treatment.Consequently an apparent increase in cell viability for drug treatmentrelative to vehicle is tabulated as a negative percentage.

Cytokine Production in LPS-Treated Sputum Macrophages from COPD Patients

Patients with COPD inhaled a nebulised solution of 3% (w/v) hypertonicsaline using an ultrasonic nebuliser (Devilbiss, Carthage, Mo.) withtidal breathing for 5 min. This procedure was repeated a maximum ofthree times until enough sputum was obtained. The sputum samples werehomogenized and mixed vigorously using a vortex mixer in 0.02% v/vdithiothreitol (DTT) solution. The samples were re-suspended in PBS (40mL) followed by centrifugation at 1500 rpm at 4° C. for 10 min to obtainsputum cell pellets. The pellets were washed with PBS (40 mL). Thesputum cells were then re-suspended in 4 mL macrophage serum-free medium(macrophage-SFM, Life technologies, containing 20 U/mL penicillin, 0.02mg/mL streptomycin and 5 μg/mL amphotericin B) and seeded on high bound96-well plate, followed by incubation for 1 h at 37° C. and at 5% CO₂ toallow the macrophages to attach to the bottom of the plate. The cells onthe plate were washed with fresh macrophage-SFM (200 μL/well) to removeneutrophils and other contaminated cells. The adherent cells (mainlysputum macrophages) on the plate were used for further analysis. Sputuminductions were conducted in Quintiles Drug Research Unit at GuysHospital and ethics approval and written informed consent was obtainedby Quintiles.

Where appropriate, 1 μL of a solution containing either the testcompound or reference article at the stated concentrations (either 0.1μg/mL, 0.01 μg/mL, or 0.001 μg/mL) or alternatively 1 μL of DMSO as thevehicle control was added to each well (200 μL in media) and the cellswere incubated for 2 h. The cells were stimulated with LPS solution (50μL, final concentration: 1 μg/mL) and incubated for 18 h at 37° C. and5% CO₂. The supernatant was then collected and kept at −80° C. Suitableluminex kits were used to measure the selected analytes. After thawingthe supernatant, the magnetic antibody beads were multiplexed andincubated in a 96-well plate with standard, background solution or theappropriate volume of sample overnight with shaking at 4° C. Afterwashing twice with 200 μL of wash buffer provided by the kit per wellusing a magnetic plate washer, the beads were incubated for 1 h at RTwith the biotin conjugated antibody solution provided by the kit withshaking. Streptavidin solution was added for 30 min with shaking at RT.After washing with 200 μL wash buffer per well, the beads wereresuspended in sheath fluid (150 μL) and analyzed immediately. The levelof each analyte in the supernatant was calculated using Xcel Fitsoftware with a 4 or 5-parameter equation using each standard curve. Theinhibitions of each cytokine production were calculated at eachconcentration by comparison with vehicle control.

Rhinovirus-Induced IL-8 Release

Human rhinovirus RV16 is obtained from the American Type CultureCollection (Manassas, Va.). Viral stocks are generated by infecting MRC5cells with HRV until 80% of the cells were cytopathic.

BEAS2B cells are infected with HRV at an MOI of 1.2 and incubated for 1h at 33° C. with gentle shaking to promote absorption. The cells arethen washed with PBS, fresh media added and the cells are incubated fora further 72 h. The supernatant is collected for assay of IL-8concentrations using a Duoset ELISA development kit (R&D systems,Minneapolis, Minn.). Compounds are added 2 h before HRV infection and 1h after infection when non-infected HRV is washed out.

Cellular Assays (not Employed in the Examples)

The following cellular assays could be employed to assess compounds ofthe present invention:

Rhinovirus-Induced IL-8 Release (Variation on the Above Method) andICAM-1 Expression

Human rhinovirus RV16 is obtained from the American Type CultureCollection (Manassas, Va.). Viral stocks are generated by infecting Helacells with HRV until 80% of the cells were cytopathic.

BEAS2B cells are infected with HRV at an MOI of 5 and incubated for 1 to2 h at 33° C. with gentle shaking to promote absorption. The cells arethen washed with PBS, fresh media added and the cells are incubated fora further 72 h. The supernatant is collected for assay of IL-8concentrations using a Duoset ELISA development kit (R&D systems,Minneapolis, Minn.).

The level of cell surface ICAM-1 expression is determined by cell-basedELISA. At 72 h after infection, cells were fixed with 4% formaldehyde inPBS. After quenching endogenous peroxidase by adding 0.1% sodium azideand 1% hydrogen peroxide, wells are washed with wash-buffer (0.05% Tweenin PBS: PBS-Tween). After blocking well with 5% milk in PBS-Tween for 1h, the cells are incubated with anti-human ICAM-1 antibody in 5% BSAPBS-Tween (1:500) overnight. Wells are washed with PBS-Tween andincubated with the secondary antibody (HRP-conjugated anti-rabbit IgG,Dako Ltd.). The ICAM-1 signal is detected by adding substrate andreading at 450 nm with a reference wavelength of 655 nm using aspectrophotometer. The wells are then washed with PBS-Tween and totalcell numbers in each well were determined by reading absorbance at 595nm after Crystal Violet staining and elution by 1% SDS solution. Themeasured OD₄₅₀₋₆₅₅ readings are corrected for cell number by dividingwith the OD₅₉₅ reading in each well. Compounds are added 2 h before HRVinfection and 1 to 2 h after infection when non-infected HRV is washedout.

LPS-Induced TNFα/IL-8 Release in PBMC Cells

Peripheral blood mononuclear cells (PBMCs) from healthy subjects areseparated from whole blood using a density gradient (Lymphoprep,Axis-Shield Healthcare). The PBMCs are seeded in 96 well plates andtreated with compounds at the desired concentration for 2 h beforeaddition of 1 ng/mL LPS (Escherichia coli 0111:B4 from Sigma Aldrich)for 24 h under normal tissue culture conditions (37° C., 5% CO₂). Thesupernatant is harvested for determination of and TNFα concentrations bysandwich ELISA (Duo-set, R&D systems) and read on the fluorescencemicroplate reader (Varloskan® Flash, ThermoFisher Scientific).

The concentration at 50% inhibition (IC₅₀) of IL-8 and TNFα productionis calculated from the close response curve.

IL-2 and IFN Gamma Release in CD3/CD28 Stimulated PBMC Cells

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells are addedto a 96 well plate pre-coated with a mixture of CD3/CD28 monoclonalantibodies (0.3 μg/mL eBioscience and 3 μg/mL BD Pharmingenrespectively). Compound at the desired concentration is then added tothe wells and the plate left for 3 days under normal tissue cultureconditions. Supernatants are harvested and IL-2 and IFN gamma releasedetermined by Sandwich ELISA (Duo-set, R&D System). The IC₅₀ isdetermined from the close response curve.

IL-1β-Induced IL-8 Release in HT29 Cells

HT29 cells, a human colon adenocarcinoma cell line, are plated in a 96well plate (24 h) and pre-treated with compounds at the desiredconcentration for 2 h before addition of 5 ng/mL of IL-1β (Abcam) for 24h. Supernatants are harvested for IL-8 quantification by Sandwich ELISA(Duo-set, R&D System). The IC₅₀ is determined from the close responsecurve.

T Cell Proliferation

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). The lymphocytefraction is first enriched for CD4+ T cells by negative magnetic cellsorting as per the manufacturer's instructions (Miltenyl Biotec130-091-155). Naïve CD4+ T cells are then separated using positivemagnetic selection of CD45RA+ cells using microbeads as per themanufacturer's instructions (130-045-901). Cells are plated at 2×10⁵cells per well in 100 μL RPMI/10% FBS on 96 well flat bottomed plate(Corning Costar). 25 μL of test compound are diluted to the appropriateconcentration (8× final conc.) in normal medium and added to duplicatewells on the plate to achieve a close response range of 0.03 ng/mL-250ng/mL. DMSO is added as a negative control. Plates are allowed topre-incubate for 2 h before stimulation with 1 μg/mL anti-CD3 (OKT3;eBioscience). After 72 h, the medium in each well is replaced with 150μL of fresh medium containing 10 μM BrdU (Roche). After 16 h, thesupernatant is removed, the plate is dried and the cells fixed by adding100 μL of fix/denature solution to each well for 20 min as per themanufacturer's instructions (Roche). Plates are washed once with PBSbefore addition of the anti-BrdU detection antibody and incubated for 90min at room temperature. Plates are then washed gently 3× with the washbuffer supplied and developed by addition of 100 μL of substratesolution. The reaction is stopped by addition of 50 μL of 1 M H₂SO₄, andread for absorbance at 450 nm on a plate reader (Varioskan® Flash,ThermoFisher Scientific). The IC₅₀ is determined from the close responsecurve.

Human Biopsy Assay

Intestinal mucosa biopsies are obtained from the inflamed regions of thecolon of IBD patients. The biopsy material is cut into small pieces (2-3mm) and placed on steel grids in an organ culture chamber at 37° C. in a5% CO₂/95% O₂ atmosphere in serum-free media. DMSO control or testcompounds at the desired concentration are added to the tissue andincubated for 24 h in the organ culture chamber. The supernatant isharvested for determination of IL-6, IL-8, IL-1β and TNFα levels by R&DELISA. Percentage inhibition of cytokine release by the test compoundsis calculated relative to the cytokine release determined for the DMSOcontrol (100%).

IL-2 and IFNγ Release in CD3/CD28 Stimulated LPMC Cells from IBDPatients

Lamina propria mononuclear cells (LPMCs) are isolated and purified frominflamed IBD mucosa of surgical specimens or from normal mucosa ofsurgical specimens as follows:

The mucosa is removed from the deeper layers of the surgical specimenswith a scalpel and cut in fragments 3-4 mm size. The epithelium isremoved by washing the tissue fragments three times with 1 mM EDTA(Sigma-Aldrich, Poole, UK) in HBSS (Sigma-Aldrich) with agitation usinga magnetic stirrer, discarding the supernatant after each wash. Thesample is subsequently treated with type 1A collagenase (1 mg/mL;Sigma-Aldrich) for 1 h with stirring at 37° C. The resulting cellsuspension is then filtered using a 100 μm cell strainer, washed twice,resuspended in RPMI-1640 medium (Sigma-Aldrich) containing 10% fetalcalf serum, 100 U/mL penicillin and 100 μg/mL streptomycin, and used forcell culture.

Freshly isolated LPMCs (2×10⁵ cells/well) are stimulated with 1 μg/mLα-CD3/α-CD28 for 48 h in the presence of either DMSO control orappropriate concentrations of compound. After 48 h, the supernatant isremoved and assayed for the presence of TNFα and IFNγ by R&D ELISA.Percentage inhibition of cytokine release by the test compounds iscalculated relative to the cytokine release determined for the DMSOcontrol (100%).

Inhibition of Cytokine Release from Myofibroblasts Isolated from IBDPatients

Myofibroblasts from inflamed IBD mucosa are isolated as follows:

The mucosa is dissected and discarded and 1 mm-sized mucosal samples arecultured at 37° C. in a humidified CO₂ incubator in Dulbecco's modifiedEagle's medium (DMEM, Sigma-Aldrich) supplemented with 20% FBS, 1%non-essential amino acids (Invitrogen, Paisley, UK), 100 U/mLpenicillin, 100 μg/mL streptomycin, 50 μg/mL gentamycin, and 1 μg/mLamphotericin (Sigma-Aldrich). Established colonies of myofibroblasts areseeded into 25-cm² culture flasks and cultured in DMEM supplemented with20% FBS and antibiotics to at least passage 4 to provide a sufficientquantity for use in stimulation experiments.

Subconfluent monolayers of myofibroblasts are then seeded in 12-wellplates at 3×10⁵ cells per well are starved in serum-free medium for 24 hat 37° C., 5% CO₂ before being cultured for 24 h in the presence ofeither DMSO control or appropriate concentrations of compound. After 24h the supernatant is removed and assayed for the presence of IL-8 andIL-6 by R&D ELISA. Percentage inhibition of cytokine release by the testcompounds is calculated relative to the cytokine release determined forthe DMSO control (100%).

Human Neutrophil Degranulation

Neutrophils are isolated from human peripheral blood as follows:

Blood is collected by venepuncture and anti-coagulated by addition of1:1 EDTA: sterile phosphate buffered saline (PBS, no Ca+/Mg+). Dextran(3% w/v) is added (1 part dextran solution to 4 parts blood) and theblood allowed to stand for approximately 20 min at RT. The supernatantis carefully layered on a density gradient (Lymphoprep, Axis-ShieldHealthcare) and centrifuged (15 min, 2000 rpm, no brake). Thesupernatant is aspirated off and the cell pellet is re-suspended insterile saline (0.2%) for no longer than 60 seconds (to lysecontaminating red blood cells). 10 times volume of PBS is then added andthe cells centrifuged (5 min, 1200 rpm). Cells are re-suspended in HBSS+(Hank's balanced salt solution (without phenol red) containingcytochalasin B (5 μg/mL) and 1 mM CaCl₂) to achieve 5×10⁶ cells/mL.

5×10⁴ cells are added to each well of a V-bottom 96 well plate andincubated (30 min, 37° C.) with the appropriate concentration of testcompound (0.3-1000 ng/mL) or vehicle (DMSO, 0.5% final conc).Degranulation is stimulated by addition of fMLP (final conc 1 μM) whichafter a further incubation (30 min, 37° C.) the cells are removed bycentrifugation (5 min, 1500 rpm) and the supernatants transferred to aflat bottom 96 well plate. An equal volume of tetramethylbenzidine (TMB)is added and after 10 min the reaction terminated by addition of anequal volume of sulphuric acid (0.5 M) and absorbance read at 450 nm(background at 655 nm subtracted). The 50% inhibitory concentration(IC₅₀) is determined from the resultant concentration-response curve.

Cell Cytotoxicity Assay

5×10⁴ TK6 cells (lymphoblastic T cell line) are added to the appropriatenumber of wells of a 96 well plate in 195 μL of media (RPMI supplementedwith 10% foetal bovine serum). 5 μL of DMSO control (final concentration0.5% v/v) or test compound (final concentration either 5 or 1 μg/mL) isadded to the wells and incubated at 37° C., 5% CO₂. After 24 h, theplate is centrifuged at 1300 rpm for 3 min and the supernatantdiscarded. Cells are then resuspended in 7.5 μg/mL propidium iodide (PI)in PBS. After 15 min, cells are analysed by flow cytometry (BD accuri).The % viability is calculated as the % of cells that are PI negative inthe test wells normalised to the DMSO control.

In Vivo Screening: Pharmacodynamics and Anti-Inflammatory Activity(Employed in the Examples)

The following in vivo screens were employed to assess compounds of thepresent invention and the results are given infra.

LPS-Induced Neutrophil Accumulation in Mice

Non-fasted Balb/c mice were closed by the intra tracheal route witheither vehicle, or the test substance at the indicated times (within therange 2-8 h) before stimulation of the inflammatory response byapplication of an LPS challenge. At T=0, mice were placed into anexposure chamber and exposed to LPS (7.0 mL, 0.5 mg/mL solution in PBSfor 30 min). After a further 8 h the animals were anesthetized, theirtracheas cannulated and BALF extracted by infusing and then withdrawingfrom their lungs 1.0 mL of PBS via the tracheal catheter. Total anddifferential white cell counts in the BALF samples were measured using aNeubaur haemocytometer. Cytospin smears of the BALF samples wereprepared by centrifugation at 200 rpm for 5 min at RT and stained usinga DiffQuik stain system (Dade Behring). Cells were counted using oilimmersion microscopy. Data for neutrophil numbers in BAL are shown asmean±S.E.M. (standard error of the mean). The percentage inhibition ofneutrophil accumulation was calculated for each treatment relative tovehicle treatment.

Cigarette Smoke Model

A/J mice (males, 5 weeks old) were exposed to cigarette smoke (4%cigarette smoke, diluted with air) for 30 min/day for 11 days using aTobacco Smoke Inhalation Experiment System for small animals (ModelSIS-CS; Sibata Scientific Technology, Tokyo, Japan). Test substanceswere administered intra-nasally (35 μL of solution in 10% DMSO/PBS) oncedaily for 3 days after the final cigarette smoke exposure. At 12 h afterthe last closing, each of the animals was anesthetized, the tracheacannulated and bronchoalveolar lavage fluid (BALF) was collected. Thenumbers of alveolar macrophages and neutrophils were determined by FACSanalysis (EPICS® ALTRA II, Beckman Coulter, Inc., Fullerton, Calif.,USA) using anti-mouse MOMA2 antibody (macrophage) or anti-mouse 7/4antibody (neutrophil). BALF was centrifuged and the supernatant wascollected. The level of keratinocyte chemoattractant (KC; CXCL1) in BALFwas quantitated using a Quantikine® mouse KC ELISA kit (R&D systems,Inc., Minneapolis, Minn., USA).

In Vivo Screening: Pharmacodynamics and Anti-Inflammatory Activity (notEmployed in the Examples)

The following in vivo screens could be employed to assess compounds ofthe present invention:

DSS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are closed by oral gavagetwice daily with either vehicle, reference item (5-ASA) or test compoundone day before (Day −1) stimulation of the inflammatory response bytreatment with DSS. On Day 0 of the study DSS (5% w/v) is administeredin the drinking water followed by BID closing of the vehicle (5 mL/kg),reference (100 mg/kg) or test compound (5 mg/kg) for 7 days. Thedrinking water with DSS is replenished every 3 days. During the studyanimals are weighed every day and stool observations are made andrecorded as a score, based on stool consistency. At the time ofsacrifice on Day +6 the large intestine is removed and the length andweight are recorded. Sections of the colon are taken for either MPOanalysis to determine neutrophil infiltration or for histopathologyscoring to determine disease severity.

TNBS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are closed by oral gavagetwice daily with either vehicle (5 mL/kg), reference item (Budesonide2.5 mg/kg) or test compound (1, 5 or 50 mg/kg) one day before (Day −1)stimulation of the inflammatory response by treatment with2,4,6-trinitrobenzenesulphonic acid (TNBS) (15 mg/mL in 50% ethanol/50%saline). On Day 0 of the study TNBS (200 μL) is administeredintra-colonically via a plastic catheter followed by BID closing of thevehicle, reference or test compound for 2 or 4 days. During the studyanimals are weighed every day and stool observations are made andrecorded as a score, based on stool consistency. At the time ofsacrifice on Day 2 (or Day 4) the large intestine is removed and thelength and weight recorded. Sections of the colon are taken for eitherMPO analysis to determine neutrophil infiltration or for histopathologyinvolving scoring to determine disease severity.

Adoptive Transfer in Mice

On study Day 0, female Balb/C mice are terminated and spleens obtainedfor CD45RB^(high) cell isolation (Using SCID IBD cell Separationprotocol). Approximately 4×10⁵ cells/mL CD45RB^(high) cells are theninjected IP (100 μL/mouse) into female SCID animals. On study Day 14,mice are weighed and randomized into treatment groups based on bodyweight. On Day 21, compounds are administered BID, via oral gavage, in apeanut oil vehicle at the close levels outlined below and a close volumeof 5 mL/kg. Treatment continues until study Day 42, at which point theanimals are necropsied 4 h after am administration. The colon length andweight is recorded and used as a secondary endpoint in the study as ameasurement of colon oedema. The colon is then divided into sixcross-sections, four of which are used for histopathology scoring(primary endpoint) and two are homogenised for cytokine analysis. Datashown is the % inhibition of the induction window between naïve animalsand vehicle animals, where higher inhibition implies closer to thenon-diseased, naïve, phenotype.

In Vitro and In Vivo Screening Results

In vitro screening results for the examples are set out in Table 2A,Table 2B, Table 3, Table 4, Table 5A, Table 5B, Table 6A and Table 6Bbelow and FIG. 1. In FIG. 1 the compound of the invention is Example 2.Comparison is made with a structurally related Reference CompoundN-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide(Example 1 of WO2010/112936), which has been previously described as apotent anti-inflammatory agent with anti-viral effects, as well as withfluticasone propionate which is a well known anti-inflammatory agent.

TABLE 2A p38 MAPKα and γ, HCK, c-Src, Syk and GSK3α Enzyme Profile ofExamples IC₅₀ Values for Enzyme Inhibition (nM) p38 p38 Example no.MAPKα MAPKγ HCK c-Src Syk GSK3α Reference 10 87 7 11 42 18 Compound 1 2567 29 98 >16703 >16703 2 26 152 55 199 >15955 >15105 3 9 222 66144 >14289 >14289 4 22 441 111 447 >15955 >4957 5 <0.48 16 <0.48<0.48 >15930 2770 6 3 37 10 24 7522 922 7 15 151 64 358 >15249 >15249 81 43 10 32 >14624 138 9 134 9242 1500 2514 >14931 3322 10 8 31 1647 >15905 >15905 11 52 682 >8886 600 >16033 >16033 12 14 198 39105 >16242 >16242 13 9 63 49 129 >16536 >14661 14 12 237 6 29 >155823367 15 96 160 15 34 >15655 3651 16 87 >7150 355 2520 >15655 >15655 17 874 17 34 >13247 2818 18 13 104 41 196 >15905 9168 19 13 229 53151 >16320 >16320 20 15 62 52 150 >16320 9043 21 5 31 12 33 >15905 158322 22 377 14 27 6698 1711 23 4 209 13 33 2153 626 24 38 334 18 42 88261129 25 7 49 5 10 2220 523 26 7 74 20 56 1584 469 27 17 376 13 42 91601029 28 5 106 11 32 >14931 5169 29 5 80 10 28 >14624 207 30 2 29 619 >15250 1488 31 4 112 59 154 >16536 11319 32 3 37 7 25 >15250 1324 333 53 11 35 >14931 5963 34 13 274 7 18 4262 1198 35 9 171 42 51 >140483430 36 19 1074 48 61 >14371 >13810 37 24 569 142 512 >15955 >10010 3814 >16268 60 153 >16268 5994 39 18 310 31 82 >15905 >15905 40 11 79 2385 >16703 8776 41 189 >15955 1428 10986 6131 3572 42 15 521 89543 >16320 6942 43 12 394 53 73 >14167 7918 44 11 454 58233 >14167 >14167 45 120 >16152 2244 7894 >16152 1898 46 85 1947 68 3856703 7052 47 87 473 110 402 4152 2800 48 91 1233 133 459 >14996 4213 4911 129 115 556 9251 4478 50 22 356 113 966 5816 7079 51 14 171 36160 >16320 >16320 52 116 >14999 316 >14999 >14999 >14999

TABLE 2B p38 MAPKα and γ Enzyme Profile of Examples p38 p38 p38 p38Example no. MAPKα MAPKγ Example no. MAPKα MAPKγ Reference 10 87Reference 10 87 Compound Compound 53 17 95 91 NT 176 54 NT 150 92 NT 11755 15 151 93 NT 103 56 21 262 94 NT 772 57 15 229 95 NT 55 58 18 435 96NT 269 59 18 105 97 NT 34 66 14 144 98 NT 116 61 5.6 32 99 NT 11 62 24560 100 NT 202 63 25 312 101 NT 374 64 9.7 39 102 NT 46 65 23 3116 103NT 72 66 28 319 104 8.9 223 67 39 345 105 <1.59 4558 68 132 624 106 3.4401 69 8.0 106 107 27 5735 70 70 372 108 17 15510 71 24 272 109 115 133072 11 118 110 1.6 23 73 19 259 111 33 125 74 43 482 112 43 277 75 17 179113 37 3203 76 15 148 114 2.0 26 77 NT 106 115 7.5 725 78 21 422 116 232818 79 <0.40 101 117 16 150 80 <0.41 54 118 5.5 115 81 NT 16 119 13 17582 NT 46 120 4.8 173 83 NT 39 121 38 79 84 NT 67 122 2779 8740 85 NT 166123 60 171 86 NT 19 124 288 >13736 87 NT 63 125 302 >13477 88 NT 233 12647 187 89 NT 42 127 6.8 93 90 NT 83 128 55 >14663 129 40 >15601 171 1249 130 31 2795 172 31 169 131 14 >15949 173 54 571 132 11 >13699 174 7.756 133 7.3 10245 175 38 >15456 134 3.8 35 176 36 458 135 52 >15244 1775.2 81 136 <0.41 41 178 5.8 36 137 6.0 >14085 179 46 >15456 13829 >15337 180 19 112 139 53 1108 181 15 64 140 29 >15244 182 44 1137 14118 438 183 38 >15480 142 5.7 78 184 19 >15898 143 19 211 185 110 2507144 63 518 186 25 >14006 145 43 260 187 16 180 146 69 1550 188 32 442147 4.1 119 189 72 579 148 13 247 190 23 232 149 13 >15873 191 47 460150 25 229 192 46 >14620 151 35 439 193 89 >14286 152 14 240 194 2078407 153 20 77 195 15 245 154 10 49 196 29 219 155 8.9 31 197 37 >15576156 21 495 198 10 111 157 23 >14881 199 11 >13774 158 435 >14993 200 131243 159 36 427 201 112 7901 160 34 510 202 19 1127 161 10 74 203 17 250162 4.7 37 204 16 330 163 19 389 205 13 263 164 6.8 2344 206 22 517 16512 128 207 30 2389 166 6.2 52 208 50 >15244 167 25 259 209 6.5 54 168 341200 210 28 509 169 26 449 211 60 582 170 35 329 212 89 >15625 213 36735 251 81 >15625 214 31 1931 252 NT >15129 215 15 >14306 253 NT 75 21615 401 254 NT 1935 217 17 424 255 NT >15504 218 28 >14085 256 NT >15408219 18 >14025 257 12 68 220 31 164 258 2.4 77 221 81 1267 259 1.2 146222 23 175 260 <0.39 47 223 11 103 261 <0.47 146 224 54 >14045 262 11174 225 14 342 263 21 218 226 35 >13774 264 23 109 227 43 >13774 265 1157 228 35 >13717 266 <0.39 51 229 27 >14104 267 <0.47 2036 230 43 >14104268 <0.42 74 231 15 95 269 <0.40 138 232 18 117 270 4.5 66 233 9.4 98271 NT 108 234 64 >15625 272 NT 4.0 235 65 >14006 273 NT 4.7 23642 >14006 274 NT 13 237 8.4 29 275 NT 129 238 19 151 276 NT 8.4 239 14130 277 NT 31 240 12 80 278 NT 197 241 3.4 48 279 NT 116 242 19 >14025280 NT 31 243 8.5 96 281 NT 289 244 3.0 46 282 NT 62 245 18 1704 283 NT35 246 58 3729 284 NT 1.7 247 7.0 61 285 NT 83 248 4.7 51 286 NT 5.8 2493.6 46 287 NT >12771 250 11 >13699 288 NT >13587 NT = not tested

TABLE 3 Inhibition of LPS Induced TNFα and IL-8 Release and PolyICInduced ICAM-Expression for Examples LPS Induced Release (nM) PolyIC/IL-8 TNFα ICAM1 (nM) IC₅₀ REC₅₀ IC₅₀ Example no. (dU937) (dU937)(BEAS2B) Reference 1.2 0.7 3.8 Compound 1 13.0 1.6 81.8 2 11.4 5.5 61.13 8.8 5.5 460.3 4 25.4 25.6 >1596 5 2.4 2.8 473.5 6 90.7 8.5 52.4 7 16.710.7 >1525 8 10.3 3.9 31.5 9 8.8 1.3 72.5 10 15.3 2.8 32.5 11 12.52.3 >1603 12 9.3 16.8 241.9 13 7.8 18.2 556.1 14 5.5 2.9 64.3 15 1.9 2.115.7 16 89.6 144.0 >1565 17 16.5 12.7 433.2 18 2.1 2.6 97.8 19 1.4 13.2339.5 20 1.3 1.3 151.9 21 7.9 0.6 76.5 22 1.6 2.1 19.6 23 6.2 3.1 33.524 4.5 3.1 55.1 25 5.8 1.4 13.1 26 14.6 4.5 972.9 27 4.0 4.3 71.2 2829.9 2.7 75.5 29 8.5 4.2 43.0 30 6.9 5.2 114.7 31 33.4 1.0 874.3 32 15.013.0 65.6 33 42.4 2.6 150.4 34 8.3 5.4 41.1 35 102.2 12.1 113.4 36 2.81.6 187.8 37 19.3 14.3 611.2 38 9.6 2.7 75.5 39 12.8 3.4 46.6 40 11.73.0 636.8 41 43.8 3.0 >1596 42 18.3 4.3 197.3 43 41.4 16.8 >1417 44 52.288.2 1154.5 45 17.1 3.5 1437.1 46 268.2 0.7 211.7 47 15.6 5.8 151.3 4816.7 0.3 92.5 49 24.3 2.3 474.5 50 30.3 7.1 >1615 51 25.7 2.2 280.652 >1500 18.7 >1500 NT = not tested

TABLE 4 Effect of examples on Cell Viability MTT Assay¹ Cell viabilityat time point indicated in d-U937 Cells Example no. 4 h 24 h Reference− + Compound 1 − − 2 − − 3 − − 4 − − 5 − + 6 − − 7 + + 8 − + 9 − − 10 −− 11 − − 12 − − 13 − − 14 − − 15 − − 16 − − 17 − − 18 − + 19 − − 20 − −21 − − 22 − − 23 − + 24 − − 25 − + 26 − + 27 − + 28 − + 29 − + 30 − − 31− − 32 − − 33 − − 34 − − 35 − − 36 − − 37 − − 38 − − 39 − − 40 − − 41 −− 42 − − 43 − − 44 − + 45 − − 46 − − 47 − − 48 − − 49 − − 50 − − 51 − −52 − − ¹Cell viability screen: −ve and +ve indicate the value is belowand above, respectively, the no significant effect threshold defined as30% inhibition at 10 μg/mL at the time point indicated.

TABLE 5A Effect of Example 1 on Cell Division Mitosis Assay Test %Inhibition at 5 μg/mL Substance in PBMC Cells Example 1 29.9 ReferenceCompound 87.9

TABLE 5B Effect of Example 2 on Cell Division Mitosis Assay Test %Inhibition at 5 μg/mL Substance in PBMC Cells¹ Example 2 18 ± 7Reference Compound 93 ± 5 ¹Mean ± SEM

TABLE 6A Effect of Example 1 and fluticasone propionate on cytokineproduction in LPS-treated sputum macrophages from COPD patients IC₅₀values (nM) and/or E max (% in parentheses)¹ for Test SubstanceIndicated Fluticasone Cells Type Cytokine Example 1 Propionate SputumIL-6 28 (60%) ND (42%) Macrophage ¹E-max values (maximum inhibition)were calculated as the % inhibition obtained at 0.1 μg/mL. ND = notdetermined (single dose tested)

TABLE 6B Effect of Example 2 and fluticasone propionate on cytokineproduction in LPS-treated sputum macrophages from COPD patients TestPercent Inhibition at 0.1 μg/mL¹ Compound IL-6 Fluticasone propionate 29± 21 Example 2 48 ± 9  ¹Mean ± SEM

Further In Vivo Studies on Example 1

Additional in vivo studies were performed on Example 1, as shown inTables 7-9 below:

TABLE 7 The Effects of Treatment with Example 1 on LPS-Induced AirwayNeutrophilia in Mice. Neutrophil numbers in BALF (×10⁵/mL) Example 1 atpre-dose time indicated (% inhibition)¹ (mg/mL) 2 hr 8 hr Vehicle 15.280.2 4.92 (67.8%) 7.59 (50.3%) ¹N = 8 per group

TABLE 8 The Effects of Treatment with Example 1 on Tobacco Smoke inMice. Cell numbers in BALF × Treatment 10⁴/mL (% inhibition) Example 1(μg/mouse) Macrophage Neutrophil Vehicle + Air 4.25 1.81 Vehicle +Tobacco Smoke 18.76 10.63 7 11.34 (51.1%) 6.04 (52.0%) 0.7 14.92 (26.5%)7.66 (33.7%) 0.07 17.27 (10.2%) 9.42 (13.7%) The data for cell numbersare shown as the mean ± SEM, N = 5-6

TABLE 9 The Effects of Treatment with Example 1 on CXCL1 (KC) release inBALF on Tobacco Smoke in Mice. Treatment CXCL1 in BALF Example 1(μg/mouse) pg/mL (% inhibition) Vehicle + Air 6.14 Vehicle + TobaccoSmoke 15.89 7  9.03 (70.3%) 0.7 12.49 (34.9%) 0.07 14.47 (14.6%) Thedata for CXCL1 level are shewn as the mean ± SEM, N = 5-6Summary of In Vitro and In Vivo Screening Results

The examples of the invention demonstrate a profile in in vitro and invive assays consistent with good anti-inflammatory activity. In mostcases they have very weak activity at Syk and GSK3a kinases and lowtoxicity in a cell viability assay (Tables 2A, 2B, 3 and 4).

Examples 1 and 2 demonstrated a similar inhibitory profile to theReference Compound in the range of kinase enzyme assays with the markedexception of the inhibitory activities against the enzymes Syk and GSK3akinases which are very much weaker than the Reference Compound (Table2A). Examples 1 and 2 demonstrated a similar profile to the ReferenceCompound in cellular assays that reveal anti-inflammatory propertiesagainst endotoxin mediated release of both TNF and IL-8 (Table 3).

In general the examples showed markedly less activity in an assay systemthat measures their impact on cell viability indicating that they arelikely to possess a superior therapeutic index over the ReferenceCompound (Table 4).

Examples 1 and 2 showed markedly less activity in an assay systems thatmeasures its impact on cell division (mitosis) further indicating thatthe compound is likely to possess a superior therapeutic index over theReference Compound (Table 5A and 5B) Examples 1 and 2 demonstratedhigher efficacy in inhibition of pro-inflammatory cytokine production insputum macrophage than fluticasone propionate, a corticosteroid (Tables6A and 6B).

Treatment of mice with Example 1 was found to produce inhibition onLPS-induced neutrophil accumulation and a time course experimentrevealed that the drug substance had a long duration of action (Table7).

Treatment of mice with Example 1 was found to produce a dose-dependentinhibition on both macrophage and neutrophil accumulation in BALFinduced by cigarette smoke (Table 8). The cigarette smoke model used forthis study is reported to be a corticosteroid refractory system,(Medicherla S. et al., J. Pharmacol. Exp. Ther., 2008, 324(3):921-9) andit was confirmed that fluticasone propionate did not inhibit eitherneutrophil or macrophage accumulation into airways at 1.75 μg/mouse (35μL, bid, i.n.), the same close that produced >80% inhibition ofLPS-induced neutrophil accumulation.

Treatment of mice with Example 1 also inhibited tobacco smoke inducedCXCL1 (KC) production in BALF in a dose-dependent manner (Table 9).

Example 2 shows dose-dependent inhibition of HRV-induced IL-8 (FIG. 1).

In summary, these results suggest that the compounds of the invention,exemplified by Examples 1 and 2 and other examples, have similaranti-inflammatory properties to the Reference Compound disclosed aboveand, advantageously, are associated with a superior therapeutic index.

The invention claimed is:
 1. A method of treatment of a conditionselected from exacerbation of COPD and exacerbation of asthma comprisingadministering to a subject in need thereof an effective amount of acompound of formula (I)

wherein: R¹ represents

Q represents N or CH; R^(2a), R^(2b) and R^(2c) are independentlyselected from hydrogen, hydroxyl, halogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,C₃₋₅cycloalkyl; —C₁₋₃alkylene-OH, —OC₂₋₃alkylene-OH, —C₁₋₆alkoxy,—C₁₋₃alkylene-N—(C₁₋₃alkyl)₂, —N(C₁₋₃alkyl)₂, —SC₁₋₃alkyl and—C₁₋₃alkylene-S—C₁₋₃alkyl; R^(2d) and R^(2e) are defined as follows:either (i) R^(2d) represents hydrogen, —C₁₋₈ alkyl in which 1 to 3carbon atoms are optionally substituted by halogen, —C₀₋₂alkylene-Cyc,—C₀₋₂alkylene-Het, —CH₂-J, —C≡C—CH₂-J, —NR³R⁴, —OR⁵ or —CN; and R^(2e)represents hydrogen or —C₁₋₆ alkyl; or (ii) R^(2e) represents—C₀₋₂alkylene-Cyc, —C₀₋₂alkylene-Het, —CO—K-Cyc, —CO—K′-Het,—CO—K′-HetAr, —CH₂-J, —CO-J′, or —C₁₋₈ alkyl in which 1 to 3 carbonatoms are optionally substituted by halogen; and R^(2d) representshydrogen or —C₁₋₆ alkyl; or (iii) R^(2d) and R^(2e) are joined andtogether represent a C₃₋₅alkylene chain in which one carbon atom of saidalkylene chain, not being in a position adjacent to the pyrazine ring,is optionally replaced by O or NR^(2f) wherein R^(2f) represents H orC₁₋₃alkyl and wherein a carbon atom of said alkylene chain is optionallysubstituted by one or more groups selected from halogen, oxo and methyl;J and J′ independently represent a C₁₋₁₀ alkyl moiety in which 1, 2 or 3carbon atoms are replaced by a heteroatom selected from O and N providedthat any two heteroatoms if present are separated by at least two carbonatoms and wherein 1 or 2 carbon atoms are optionally substituted by oxoand which moiety is optionally substituted by 1 to 3 halogen groupsprovided that J′ does not represent OH; K and K′ independently representa bond or a C₁₋₁₀ alkylene chain in which 1, 2 or 3 carbon atoms areoptionally replaced by a heteroatom selected from O and N provided thatany two heteroatoms if present are separated by at least two carbonatoms and provided that neither K nor K′ represents O; R³ and R⁴independently represent H or —C₁₋₈ alkyl optionally substituted by 1 to3 groups selected from hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl andhalogen and wherein 1 or 2 carbon atoms of said alkyl are optionallysubstituted by oxo; or R³ and R⁴ are joined such that —NR³R⁴ togetherrepresents a 4-7 membered heterocyclic ring optionally substituted byone to three groups selected from C₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy,hydroxyC₁₋₃alkyl and halogen in which a carbon atom separated by atleast two carbon atoms from the nitrogen atom is optionally replaced bya heteroatom selected from O and N; and wherein a methylene group isoptionally substituted by oxo; or R³ represents C₃₋₆cycloalkyl and R⁴represents hydrogen; R⁵ represents —C₁₋₈ alkyl optionally substituted by1 to 3 groups selected from hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl andhalogen and wherein 1 to 3 carbon atoms are optionally substituted byhalogen; Het represents a 4 to 7 membered non-aromatic heterocyclic ringcontaining 1 or 2 heteroatoms selected from O, S and N or an 8 to 10membered non-aromatic bicyclic heterocyclic ring containing 1, 2 or 3heteroatoms selected from O, S and N in either case optionallysubstituted by one to three groups selected from C₁₋₃alkyl, hydroxyl,C₁₋₃alkoxy, hydroxyC₁₋₃alkyl-, C₁₋₃haloalkyl, halogen, oxo,—N(C₁₋₃alkyl)₂, —C(═O)C₁₋₃alkyl, —C(═O)OC₁₋₃alkyl, —C₁₋₃alkylene-N—(C₁₋₃alkyl)₂, —C₁₋₃ alkylene-O—C₁₋₃alkyl, C₃₋₆cycloalkyl anda 4-6 membered non-aromatic heterocyclic ring containing 1 or 2heteroatoms selected from O, S and N optionally substituted by methyl,provided that Het is not directly attached to the pyrazine ring via aheteroatom and wherein a methylene group is optionally substituted byoxo; Cyc represents a 3 to 7 membered non-aromatic carbocyclic ringoptionally substituted by 1 to 3 groups selected from C₁₋₃alkyl,hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and halogen and wherein amethylene group is optionally substituted by oxo; and HetAr represents a5- or 6 membered heteroaromatic ring containing 1 to 3 heteroatomsselected from O, N and S and optionally substituted by one to threegroups selected from C₁₋₃alkyl, hydroxyl, C₁₋₃alkoxy, hydroxyC₁₋₄alkyl-,halogen and C₁₋₃haloalkyl; or a pharmaceutically acceptable saltthereof.
 2. The method of claim 1, wherein the exacerbation of COPD orexacerbation of asthma is a virally induced exacerbation.
 3. The methodof claim 1, wherein the condition is exacerbation of COPD.
 4. The methodof claim 1, wherein the COPD is selected from a group consisting ofchronic bronchitis and emphysema.
 5. The method of claim 1, wherein theasthma is pediatric asthma.
 6. The method of claim 1, wherein thecompound of formula (I) or a pharmaceutically acceptable salt thereof isadministered as a dry-powder formulation for inhalation.
 7. The methodof claim 6, wherein the dry-powder formulation for inhalation compriseslactose.
 8. The method of claim 1, wherein the compound of formula (I)is in its free base form.
 9. The method of claim 1, wherein the compoundof formula (I) is in anhydrous solid crystalline form.